Phenylalanine derivatives

ABSTRACT

Specified phenylalanine derivatives and analogues thereof have an antagonistic activity to α 4 integrin. They are used as therapeutic agents for various diseases concerning α 4 integrin.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to new phenylalanine derivativesand the use of the phenylalanine derivatives as medicines. It wasreported that α 4 integrins participate in diseases in which α 4integrin-depending adhesion process participates in the pathology, suchas inflammatory diseases, rheumatoid arthritis, inflammatory boweldiseases, systemic erythematodes, multiple sclerosis, Sjogren'ssyndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases,arterial sclerosis, restenosis, tumor proliferation, tumor metastasisand transplantation rejection. The compounds of the present inventionhaving an antagonistic effect on the α 4 integrins are usable astherapeutic agents or preventive agents for the above-describeddiseases.

[0002] In the inflammatory reactions, it is generally understood thatwhen a microorganism invades a tissue or when the tissue is injured,leukocytes play an important role for the exclusion of the microorganismor for the reparation of the injured tissue. It is also widelyunderstood that in such cases, leukocytes usually circulating in theblood must pass through the vascular wall and be newly supplied to theinjured tissue. It has been elucidated that the infiltration of theleukocytes from the blood vessel into the tissue is carried out byintegrin molecules which are a group of heterodimeric proteinsexpressing on the leukocytes. The integrin molecules are classified intoat least 8 subfamilies (β 1 through β 8 subfamilies) depending on the βchains thereof. Known typical subfamilies are β 1 and β 3 subfamiliesinvolved in the adhesion of cell ingredients to the extracellularmatrixes such as collagen and fibronectin; β 2 subfamily involved incell-to-cell adhesion in the immune system; and β 7 subfamily whichmainly participates in the infiltration of leukocytes into mucosaltissues (Shimizu et al., Adv. Immunol. 72: 325-380, 1999). As for theabove-described α 4 integrins, two kinds of molecules thereof are known.They are VLA-4 (very late antigen-4) molecule belonging to the β 1subfamily and comprising α 4 β 1 chain and LPAM-1 (lymphocyte Peyer'spatch HEV adhesion molecule-1) molecule belonging to the β 7 subfamilyand comprising α 4 β 7 chain. Usually most of leukocytes circulating inthe blood have only a low adhesion affinity for the vascular-endotheliumcells and they cannot move out of the blood vessel. On the other hand,lymphocytes mainly comprising T cells and B cells are capable of movingout of the blood vessel by a so-called lymphocyte homing phenomenonwherein they move from the blood into the lymphoid tissue through theblood vessel wall and then they return into the blood through the lymphvessel under the physiological conditions. It is known that LPAM-1molecules participate in the lymphocyte homing into the lymphoid tissueof an bowel tract such as Peyer's patch (Butcher et al., Adv. Immunol.72: 209-253, 1999). On the other hand, when an inflammation occurs, thevascular-endothelium cells are activated by cytokine and chemokinereleased from the inflamed tissue, the expression of a group of cellsurface antigens (adhesion molecules) participating in the adhesion ofleukocytes to the vascular-endothelium cells is caused, and a lot ofleukocytes infiltrate out of the blood vessel toward the inflamed tissuethrough the adhesion molecules.

[0003] As the cell surface antigens on the vascular-endothelium cellsparticipating in the adhesion of the leukocytes, there have been knownE-selectin (adhesion molecule mainly participating in the adhesion ofneutrophilic leukocytes), ICAM-1 and VCAM-1 mainly participating in theadhesion of lymphocytes, and MAdCAM-1 mainly participating in theadhesion of lymphocytes in the lymphoid tissue of an bowel tract such asPeyer's patch (Shimizu et al., Adv. Immunol. 72: 325-380, 1999). It wasreported that in those adhesion molecules, VCAM-1 acts as a ligand ofboth VLA-4 and LPAM-1 and that MAdCAM-1 acts as the ligand of LPAM-1. Asa ligand of both VLA-4 and LPAM-1, fibronectin which is a kind ofextracellular matrixes is also known (Shimizu et al., Adv. Immunol. 72:325-380, 1999). The β-1 integrin subfamily to which VLA-4 belongscomprises at least 6 integrins (VLA-1 to VLA-6) using extracellularmatrixes such as fibronectin, collagen and laminin as the ligands. Manyof integrins using extracellular matrixes as the ligands, such as VLA-5,β-3 subfamily and β-5 subfamily, recognize arginine—glycine—asparticacid (RGD) sequence in fibronectin, vitronectin, tenascin andosteopontin. On the other hand, in the interaction of VLA-4 andfibronectin, the RGD sequence does not participate but a CS-1 peptidesegment comprising leucine—aspartic acid—valine (LDV) as the coresequence participates (Pulido et al., J. Biol. Chem. 266: 10241-10245,1991). Clements et al. found a sequence similar to LDV in amino acidsequences of VCAM-1 and MAdCAM-1. It has been elucidated that a variantobtained by partially modifying the CS-1-like sequence of VCAM-1 andMAdCAM-1 molecules cannot bound to VLA-4 or LPAM-1 (Clements et al., J.Cell Sci. 107: 2127-2135, 1994, Vonderheide et al., J. Cell. Biol. 125:215-222, 1994, Renz et al., J. Cell. Biol. 125: 1395-1406, 1994, andKilger et al., Int. Immunol. 9: 219-226, 1997). Thus, it was found thatthe CS-1-like sequence is important for the binding of VLA-4/LPAM-1 andVCAM-1/MAdCAM-1.

[0004] It was reported that the same cyclic peptide having the CS-1-likestructure is antagonistic both to the binding of VLA-4 or LPAM-1 withVCAM-1, MAdCAM-1 or CS-1 peptide (Vanderslice et al., J. Immunol. 158:1710-1718, 1997). The above-described facts indicate that all theinteractions of α 4 integrin and VCAM-1, MAdCAM-1 or fibronectin can beblocked by using a suitable α 4 integrin antagonist (the term “α 4integrin antagonist” herein indicates a substance antagonistic to α 4 β1 and/or α 4 β 7 integrin).

[0005] It is also known that the expression of VCAM-1 invascular-endothelium cells is caused by inflammatory factors such asLPS, TNF-α or IL-1 and that when the inflammation occurs, theinfiltration of the leukocytes from the blood vessel into the tissue iscarried out by the VLA-4/VCAM-1 adhesion mechanism (Elices, Cell 60:577-584, 1990, Osborn et al., Cell 59: 1203-1211, 1989 and Issekutz etal., J. Eex. Med. 183: 2175-2184, 1996). Because VLA-4 is expressed onthe surfaces of activated lymphocytes, monocytes, eosinophil, mast cellsand neutrophil, the adhesion mechanism of VLA-4/VCAM-1 plays animportant role for the infiltration of those cells into the inflamedtissue. It was reported that VLA-4 is expressed on various sarcoma cellssuch as melanoma cells, and it was also elucidated that the adhesionmechanism of VLA-4/VCAM-1 participates in the metastasis of thesetumors. By investigating the expression of VCAM-1 in variouspathological tissues, it was made apparent that the adhesion mechanismof this VLA-4/VCAM-1 participates in various pathological stages.Namely, it was reported that in addition to the activatedvascular-endothelium cells, the expression of VCAM-1 is increased in theinflamed tissues in the patients with autoimmune diseases such asrheumatoid synovial membrane (van Dinther-Janssen, J. Immunol. 147:4207-4210, 1991 and Morales-Ducret et al., J. Immunol. 149: 1424-1431,1992), lungs and respiratory tract epithelium in asthma (ten Hacken etal., Clin. Exp. Allergy 12: 1518-1525, 1998) and allergic diseases(Randolph et al., J. Clin. Invest. 104: 1021-1029, 1999), systemicerythematodes (Takeuchi et al., J. Clin. Invest. 92: 3008-3016, 1993),Sjogren's syndrome (Edwards et al., Ann. Rheum. Dis. 52: 806-811, 1993),multiple sclerosis (Steffen et al., Am. J. Pathol. 145: 189-201, 1994)and psoriasis (Groves et al., J. Am. Acad. Dermatol. 29: 67-72, 1993);atherosclerotic plagues (O'Brien et al., J. Clin. Invest. 92: 945-951,1993), bowel tissues of the patients with inflammatory bowel diseasessuch as Crohn's disease and ulcerative colitis (Koizumi et al.,Gastroenterol. 103: 840-847, 1992 and Nakamura et al., Lab. Invest. 69:77-85, 1993), inflamed tissue of Langerhans island of patients withdiabetes (Martin et al., J. Autoimmun. 9: 637-643, 1996) and implantsduring the rejection of transplantation of heart or kidney (Herskowitzet al. Am. J. Pathol. 145: 1082-1094, 1994 and Hill et al., Kidney Int.47: 1383-1391, 1995). The adhesion mechanism of VLA-4/VCAM-1participates in these various diseases.

[0006] There are many reports showing that in vivo administration ofVLA-4 or VCAM-1 antibody was effective in improving the diseases ofanimal models with those inflammatory diseases. Concretely, Yednock etal. and Baron et al. reported that the in vivo administration of anantibody against α 4 integrins was effective in controlling theincidence rate or in controlling encephalomyelitis in the experimentalautoimmune encephalomyelitis models, i.e. multiple sclerosis models(Yednock et al., Nature 356: 63-66, 1992 and Baron et al., J. Exp. Med.177: 57-68, 1993). Zeider et al. reported that in vivo administration ofan antibody against α 4-integrin was effective in controlling theincidence rate of mouse collagen arthritis (rheumatism models) (Zeidleret al., Autoimmunity 21: 245-252, 1995). The therapeutic effect of anantibody against a 4-integrin in asthma models was reported by Abrahamet al. and Sagara et al. (Abraham et al., J. Clin. Invest. 93: 776-787,1994 and Sagara et al., Int. Arch. Allergy Immunol. 112: 287-294, 1997).The effect of an antibody against a 4-integrin in inflammatory boweldisease models was reported by Podolsky et al. (Podolsky et al., J.Clin. Invest. 92: 372-380, 1993). The effect of an antibody against a4-integrin and that against VCAM antibody in insulin-dependent diabetesmodels were reported by Baron et al. (Baron et al., J. Clin. Invest. 93:1700-1708, 1994). It was made apparent with baboon models that therestenosis of a blood vessel after an angioplasty carried out because ofarteriosclerosis can be inhibited by the administration of a 4 integrinantibody (Lumsden et al., J. Vasc. Surg. 26: 87-93, 1997). It was alsoreported that a 4 integrin or VCAM antibody is effective in inhibitingthe rejection of an implant or inhibiting metastasis of a cancer (Isobeet al., J. Immunol. 153: 5810-5818, 1994 and Okahara et al., Cancer Res.54: 3233-3236, 1994).

[0007] As described above, unlike VCAM-1, MAdCAM-1 which is a ligand ofLPAM-1 is constantly expressed on high endothelial venules (HEV) in thebowel mucous membrane, mesenteric lymph nodes, Peyer's patch and spleenand it participates in the homing of mucosal lymphocytes. It is alsoknown that LPAM-1/MAdCAM-1 adhesion mechanism not only has physiologicalroles in the homing of the lymphocytes but also participates in somepathological processes. Briskin et al reported an increase in theexpression of MAdCAM-1 in inflamed regions in bowel tracts of patientswith inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis (Briskin et al., Am. J. Pathol. 151: 97-110, 1997). Hanninen etal. reported that induction of the expression is observed in an inflamedtissue of Langerhans island which is a model of an insulin-dependentdiabetes (Hanninen et al., J. Immunol. 160: 6018-6025, 1998). The factthat LPAM-1/MAdCAM-1 adhesion mechanism participates in the progress ofdiseases is apparent from the fact that conditions of mouse models withinflammatory bowel disease (Picarella et al., J. Immunol. 158:2099-2106, 1997) and the above-described NOD mouse models are improvedby the in vivo administration of antibody to MAdCAM or antibody to β-7integrin (Hanninen et al., J. Immunol. 160: 6018-6025, 1998 and Yang etal., Diabetes 46: 1542-1547, 1997).

[0008] The above-described facts indicate the possibility of employingthe blocking of VLA-4/VCAM-1, LPAM-1/VCAM-1 or LPAM-1/MAdCAM-1 adhesionmechanism by a suitable antagonist is effective in treating the chronicinflammatory diseases described above. The use of the antibody againstVLA-4 as the VLA-4 antagonist is described in WO 93/13798, WO 93/15764,WO 94/16094 and WO 95/19790. Peptide compounds as VLA-4 antagonists aredescribed in WO 94/15958, WO 95/15973, WO 96/00581 and WO 96/06108.Amino acid derivatives usable as VLA-4 antagonists are described in WO99/10313 and WO 99/36393. However, none of them is practically used forthe therapeutic treatment at present because of the lack of oralbioavailability and immunogenic properties during the use of them for along period of time.

DISCLOSURE OF THE INVENTION

[0009] An object of the present invention is to provide new compoundshaving α 4 integrin antagonistic effect.

[0010] Another object of the present invention is to provide apharmaceutical composition containing such new compounds.

[0011] Still another object of the present invention is to provide α 4integrin antagonists.

[0012] A further object of the present invention is to providetherapeutic agents or preventive agents for diseases in which α 4integrin-depending adhesion process participates in the pathology, suchas inflammatory diseases, rheumatoid arthritis, inflammatory boweldiseases, systemic erythematodes, multiple sclerosis, Sjogren'ssyndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases,arterial sclerosis, restenosis, tumor proliferation, tumor metastasisand transplantation rejection.

[0013] For the purpose of solving the above-described problems, theinventors have synthesized various phenylalanine derivatives andexamining α 4 integrin antagonistic activities thereof, and theinventors have found that specified, new phenylalanine derivatives,particularly compounds of the following general formula (1) wherein Zrepresents a group of the formula: —C(═O)— or the like have an excellentα 4 integrin antagonistic activity. The present invention has beencompleted on the basis of this finding.

[0014] Namely, the present invention provides phenylalanine derivativesof the following general formula (1) and pharmaceutically acceptablesalts thereof:

[0015] wherein X represents an interatomic bond, —O—, —O—SO₂—, —NR¹—,—NR¹—(═O)—, —NR¹—SO₂—, —NR¹—C(═O)—NH—, —NR¹—C(═S)—NH— or —C(═O)— whereinR¹ represents a hydrogen atom, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s),

[0016] Y represents —C(═O)—, —S(═O)— or —SO₂—,

[0017] Z represents —C(═O)—, —S(═O)— or —SO₂—,

[0018] A represents a group of the following general formula (2), agroup of any of the following general formulae (2-1) to (2-5), a loweralkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, an arylgroup, a heteroaryl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with a group of general formula(2), a lower alkyl group substituted with an aryl group(s), a loweralkyl group substituted with a heteroaryl group(s), a lower alkenylgroup substituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s) or a lower alkynyl groupsubstituted with a heteroaryl group(s):

[0019] wherein R², R³, R⁴, R⁵ and R⁶ may be the same or different fromone another, and each represent a hydrogen atom, a halogen atom, ahydroxyl group, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkoxyl group, a lower alkoxyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkoxyl group substituted with an aryl group(s), alower alkoxyl group substituted with a heteroaryl group(s), acycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group:

[0020] wherein Arm represents benzene ring or an aromatic ringcontaining 1, 2, 3 or 4 hetero atoms selected from among oxygen, sulfurand nitrogen atoms,

[0021] R⁹ represents oxygen atom, a substituted or unsubstituted iminogroup or sulfur atom, R¹⁰, R¹¹, R¹² and R¹³ may be the same or differentfrom one another and each represent a hydrogen atom, a halogen atom, ahydroxyl group, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkoxyl group, a lower alkoxyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkoxyl group substituted with an aryl group(s), alower alkoxyl group substituted with a heteroaryl group(s), acycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group,

[0022] R¹⁴, R¹⁵, R¹⁶ and R¹⁷ may be the same or different from oneanother and each represent a hydrogen atom, a halogen atom, a hydroxylgroup, a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkoxyl group, a lower alkoxyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkoxyl group substituted with an aryl group(s), alower alkoxyl group substituted with a heteroaryl group(s), acycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group,

[0023] R²⁰ represents oxygen atom, a substituted or unsubstituted iminogroup or sulfur atom,

[0024] R¹⁸ and R¹⁹ may be the same or different from each other and eachrepresent a hydrogen atom, a lower alkyl group, a lower alkenyl group, alower alkynyl group, a cycloalkyl group which may contain a heteroatom(s) in the ring thereof, an aryl group, a heteroaryl group, a loweralkyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkyl group substituted withan aryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group, a halogeno-lower alkenyl group,a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group or asubstituted or unsubstituted amino-lower alkyl group, or R¹⁸ and R¹⁹ maybe bonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms, and the substituents of the ring include ahydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group,

[0025] R²³ represents oxygen atom, a substituted or unsubstituted iminogroup or sulfur atom,

[0026] R²¹ and R²² may be the same or different from each other and eachrepresent a hydrogen atom, a halogen atom, a hydroxyl group, a loweralkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, an arylgroup, a heteroaryl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s), a loweralkyl group substituted with a heteroaryl group(s), a lower alkoxylgroup, a lower alkoxyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkoxylgroup substituted with an aryl group(s), a lower alkoxyl groupsubstituted with a heteroaryl group(s), a cycloalkyloxy group which maycontain a hetero atom(s) in the ring thereof, an aryloxy group, aheteroaryloxy group, a hydroxy-lower alkyl group, a hydroxy-loweralkenyl group, a hydroxy-lower alkoxyl group, a halogeno-lower alkylgroup, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group,nitro group, cyano group, a substituted or unsubstituted amino group,carboxyl group, a lower alkyloxycarbonyl group, a substituted orunsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, alower alkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group,

[0027] R²⁴ and R²⁵ may be the same or different from each other and eachrepresent a hydrogen atom, a halogen atom, a hydroxyl group, a loweralkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, an arylgroup, a heteroaryl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s), a loweralkyl group substituted with a heteroaryl group(s), a lower alkoxylgroup, a lower alkoxyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkoxylgroup substituted with an aryl group(s), a lower alkoxyl groupsubstituted with a heteroaryl group(s), a cycloalkyloxy group which maycontain a hetero atom(s) in the ring thereof, an aryloxy group, aheteroaryloxy group, a hydroxy-lower alkyl group, a hydroxy-loweralkenyl group, a hydroxy-lower alkoxyl group, a halogeno-lower alkylgroup, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group,nitro group, cyano group, a substituted or unsubstituted amino group,carboxyl group, a lower alkyloxycarbonyl group, a substituted orunsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, alower alkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group,

[0028] B represents hydroxyl group, a lower alkoxyl group orhydroxyamino group,

[0029] C represents a hydrogen atom, a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a lower alkyl group substitutedwith a cycloalkyl group(s) which may contain a hetero atom(s) in thering thereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s),

[0030] D and E may be the same or different from each other and eachrepresent a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group, a lower alkoxy-lower alkylgroup, a hydroxy-lower alkyl group, a lower alkylthio-lower alkyl group,a mercapto-lower alkyl group or a substituted or unsubstitutedamino-lower alkyl group, or D and E may be bonded together to form aring which may contain one or two oxygen, nitrogen or sulfur atoms,

[0031] F and G may be the same or different from each other and eachrepresent hydrogen atom, a lower alkyl group, a lower alkenyl group, alower alkynyl group, a cycloalkyl group which may contain a heteroatom(s) in the ring thereof, an aryl group, a heteroaryl group, a loweralkyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkyl group substituted withan aryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group or a hydroxy-lower alkyl group,or F and G may be bonded together to form a ring which may contain oneor two oxygen, nitrogen or sulfur atoms,

[0032] n represents an integer of 0 to 2,

[0033] K represents OR⁷, NR⁷R⁸, NHNR⁷R⁸, NR⁷NHR⁸, SR⁷ or R⁷ wherein R⁷and R⁸ may be the same or different from each other and each represent ahydrogen atom, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group, a halogeno-lower alkenyl group,a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group or asubstituted or unsubstituted amino-lower alkyl group, or R⁷ and R⁸ maybe bonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms; and the substituents of the ring include ahydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and

[0034] J and J′ may be the same or different from each other and eachrepresent a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkyloxy group or nitro group.

[0035] The present invention provides a pharmaceutical composition andan α 4 integrin antagonist containing the above-described phenylalaninederivative or a pharmaceutically acceptable salt thereof as the activeingredient.

[0036] The present invention also provides a therapeutic agent orpreventive agent, containing the phenylalanine derivative or apharmaceutically acceptable salt thereof as the active ingredient, fordiseases in which α 4 integrin-depending adhesion process participatesin the pathology, such as inflammatory diseases, rheumatoid arthritis,inflammatory bowel diseases, systemic lupus erythematodes, multiplesclerosis, Sjogren's syndrome, asthma, psoriasis, allergy, diabetes,cardiovascular diseases, arterial sclerosis, restenosis, tumorproliferation, tumor metastasis and transplantation rejection.

BEST MODE FOR CARRYING OUT THE INVENTION

[0037] The term “lower” in, for example, a lower alkyl group indicatesthat the group has 1 to 6 carbon atoms. Alkyl groups per se and alsoalkyl groups in alkenyl groups, alkynyl groups, alkoxyl groups,alkylthio groups, alkanoyl groups and alkylamino groups, alkenyl groupsand alkynyl groups may be either linear or branched. Examples of thesealkyl groups are methyl group, ethyl group, propyl group, isopropylgroup, butyl group, secondary butyl group, tertiary butyl group, pentylgroup and hexyl group. The alkenyl groups are, for example, vinyl group,propenyl group, butenyl group and pentenyl group. The alkynyl groupsinclude ethynyl group, propynyl group and butynyl group. The cycloalkylgroups indicate substituted or unsubstituted cycloalkyl groups such ascyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, norbornyl group, adamantyl group and cyclohexenyl group. Thealkoxyl groups include methoxyl group, ethoxyl group, propyloxy group,isopropyloxy group, etc. The hetero atoms include nitrogen, oxygen,sulfur, etc. The halogen atoms are fluorine, chlorine, bromine andiodine. The halogenoalkyl groups include chloromethyl group,trichloromethyl group, trifluoromethyl group, trifluoroethyl group,pentafluoroethyl group, etc. The halogenoalkoxyl groups includetrichloromethoxyl group, trifluoromethoxyl group, etc. The hydroxyalkylgroups include hydroxymethyl group, hydroxyethyl group, etc. Thecycloalkyl groups which may contain a hetero atom(s) in the ring thereofmay be either substituted or unsubstituted. Examples of them includepiperidyl group, piperazinyl group, morpholinyl group, pyrrolidinylgroup, tetrahydrofuranyl group and groups of above general formula(2-1), (2-2), (2-3), (2-4) or (2-5).

[0038] In the present specification, the aryl groups are bothsubstituted and unsubstituted aryl groups such as phenyl group,1-naphthyl group and 2-naphthyl group. They are preferably phenyl groupand substituted phenyl group, and the substituents are particularlypreferably halogen atoms, alkoxyl groups, alkyl groups, hydroxyl group,halogenoalkyl groups, halogenoalkoxyl groups, nitro group and phenylgroup. The heteroaryl groups are both substituted and unsubstitutedheteroaryl groups such as pyridyl group, pyrimidinyl group, furyl group,thienyl group, indolyl group, quinolyl group and isoquinolyl group.Preferred heteroaryl groups are pyridyl group, pyrimidinyl group, furylgroup, thienyl group and substituted pyridyl, pyrimidinyl, furyl andthienyl groups. Particularly preferred substituents are halogen atoms,alkoxyl groups, alkyl groups, hydroxyl group, halogenoalkyl groups,halogenoalkoxyl groups, lower alkylthio groups, lower alkylsulfinylgroups, lower alkylsulfonyl groups and substituted or unsubstitutedamino groups. The lower alkyl groups substituted with an aryl group(s)include, for example, benzyl group and substituted benzyl groups.Particularly preferred substituents are halogen atoms, alkoxyl groups,alkyl groups, hydroxyl group, halogenoalkyl groups, halogenoalkoxylgroups, substituted or unsubstituted amino groups and alkylthio groups.The lower alkyl groups substituted with a heteroaryl group(s) include,for example, pyridylmethyl group, and particularly preferredsubstituents thereof are halogen atoms, alkoxyl groups, alkyl groups,hydroxyl group, halogenoalkyl groups and halogenoalkoxyl groups. Thealkanoyl groups include, for example, formyl groups, acetyl groups,propanoyl group, butanoyl group and pivaloyl group. The aroyl groupsinclude, for example, substituted or unsubstituted benzoyl group andpyridylcarbonyl group, and the substituents thereof are particularlypreferably halogen atoms, alkoxyl groups, alkyl groups, hydroxyl group,halogenoalkyl groups and halogenoalkoxyl groups. The halogenoalkanoylgroups include, for example, trichloroacetyl group and trifluoroacetylgroup. The alkylsulfonyl groups include, for example, methanesulfonylgroup, ethanesulfonyl group, etc. The arylsulfonyl groups include, forexample, benzenesulfonyl group and p-toluenesulfonyl group. Theheteroarylsulfonyl groups include, for example, pyridylsulfonyl group.The halogenoalkylsulfonyl groups include, for example,trifluoromethanesulfonyl group. The alkyloxycarbonyl groups include, forexample, methoxycarbonyl group, ethoxycarbonyl group andtert-butoxycarbonyl group. The aryl-substituted alkoxycarbonyl groupsinclude, for example, benzyloxycarbonyl group and9-fluorenylmethoxycarbonyl group. The substituted carbamoyl groupsinclude, for example, methylcarbamoyl group, phenylcarbamoyl group andsubstituted phenylcarbamoyl group, and the substituents thereof areparticularly preferably halogen atoms, alkoxyl groups, alkyl groups,hydroxyl group, halogenoalkyl groups and halogenoalkoxyl groups. Thesubstituted thiocarbamoyl groups include, for example,methylthiocarbamoyl group, phenylthiocarbamoyl group and substitutedphenylthiocarbamoyl groups, and the substituents thereof areparticularly preferably halogens, alkoxyl groups, alkyl groups, hydroxylgroup, halogenoalkyl groups and halogenoalkoxyl groups. The substituentsof the substituted amino groups herein include lower alkyl groups, loweralkyl groups substituted with an aryl group, lower alkyl groupssubstituted with a heteroaryl group, lower alkanoyl groups, aroylgroups, halogeno-lower alkanoyl groups, lower alkylsulfonyl groups,arylsulfonyl groups, heteroarylsulfonyl groups, halogenoalkylsulfonylgroups, lower alkyloxycarbonyl groups, aryl-substituted loweralkyloxycarbonyl groups, substituted or unsubstituted carbamoyl groupsand substituted or unsubstituted thiocarbamoyl groups.

[0039] The group represented by X in the above general formula (1) ispreferably an interatomic bond, —O—, —O—SO₂—, —NR¹—, —NR¹—C(═O)—,—NR¹—SO₂— or —C(═O)—. The group represented by X is particularlypreferably an interatomic bond, —O— or —NR¹—C(═O)—.

[0040] The group represented by Y is preferably —C(═O)—.

[0041] The group represented by Z is preferably —C(═O)— or —SO₂—. It isparticularly preferably —C(═O).

[0042] In the groups represented by A, the cycloalkyl groups which maycontain a hetero atom(s) in the ring thereof, aryl groups and heteroarylgroups are either substituted or unsubstituted. The substituents thereofare those described above with reference to R² to R⁶. The groupsrepresented by A are preferably groups of general formula (2), loweralkyl groups, lower alkenyl groups, lower alkynyl groups, cycloalkylgroups which may contain a hetero atom(s) in the ring thereof, arylgroups, heteroaryl groups, lower alkyl groups substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, lower alkyl groups substituted with a group of general formula(2), lower alkyl groups substituted with an aryl group(s) and loweralkyl groups substituted with a heteroaryl group(s). The groupsrepresented by A are particularly preferably lower alkyl groupssubstituted with a group of general formula (2), groups represented bygeneral formulae (2-1), (2-2), (2-3), (2-4) or (2-5) and substitutedheteroaryl groups. Among them, the lower alkyl groups substituted with agroup of general formula (2), heteroaryl groups and groups representedby general formula (2-1) are preferred.

[0043] The group represented by B is preferably a hydroxyl group.

[0044] The group represented by C is preferably a hydrogen atom.

[0045] In the groups represented by D, E, F or G, the cycloalkyl groupswhich may contain a hetero atom(s) in the ring thereof, aryl groups andheteroaryl groups are either unsubstituted or substituted, and thesubstituents are those described above with reference to R² to R⁶. Thegroups represented by D or E are preferably lower alkyl groups,particularly ethyl group. It is also preferred that D and E are bondedto each other to form a ring which may contain 1 or 2 oxygen atoms,nitrogen atoms or sulfur atoms. The groups represented by F or G ispreferably hydrogen atom or lower alkyl groups.

[0046] n is preferably an integer of 0.

[0047] In the groups represented by R⁷ or R⁸ among those represented byK, the cycloalkyl groups which may contain a hetero atom(s) in the ringthereof, aryl groups and heteroaryl groups are either substituted orunsubstituted, and the substituents are those described above withreference to R² to R⁶.

[0048] As the groups represented by K, those represented by NR⁷R⁸ orNHNR⁷R⁸ are preferred. R⁷ and R⁸, which may be the same or differentfrom each other, are each preferably hydrogen atom, a lower alkyl group,a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), or a lower alkyl group substituted with a heteroarylgroup(s). It is also preferred that R⁷ and R⁸ are bonded to each otherto form a ring which may contain 1 or 2 oxygen atoms nitrogen atoms orsulfur atoms. The substituents of the ring are preferably hydrogenatoms, halogen atoms, hydroxyl groups, lower alkyl groups, aryl groups,heteroaryl groups, lower alkyl groups substituted with an aryl group,lower alkanoyl groups, aroyl groups, lower alkyloxy groups, nitrogroups, cyano groups, substituted or unsubstituted amino groups,carboxyl groups, lower alkoxycarbonyl groups, lower alkoxycarbonylgroups substituted with an aryl group(s), substituted or unsubstitutedcarbamoyl groups, substituted or unsubstituted thiocarbamoyl groups,lower alkylthio groups, lower alkylsulfonyl groups and substituted orunsubstituted sulfamoyl groups.

[0049] As the groups represented by K, those represented by NR⁷R⁸ areparticularly preferred. In the group represented by NR⁷R⁸, it ispreferred that R⁷ and R⁸ are bonded to each other to form a ring.Examples of the groups K of formula NR⁷R⁸ wherein R⁷ and R⁸ togetherform a ring are piperidine-1-yl group, piperazine-1-yl group,morpholine-4-yl group and pyrrolidine-1-yl group.

[0050] Groups represented by J or J′ is preferably a hydrogen atom.

[0051] The substituents of R² to R⁶ are more preferably hydrogen atoms,halogen atoms, hydroxyl groups, lower alkyl groups, lower alkoxylgroups, halogeno-lower alkyl groups and halogeno-lower alkoxyl groups.

[0052] When the group K is represented by NR⁷R⁸, the groups R⁷ and R⁸are each more preferably a lower alkyl group, an aryl group or asubstituted aryl group, and the substituents of the aryl group arepreferably hydrogen atoms, halogen atoms, hydroxyl groups, lower alkylgroups, lower alkoxyl groups, halogeno-lower alkyl groups andhalogeno-lower alkoxyl groups. When R⁷ and R⁸ in N R⁷R⁸ are bonded toeach other to form a ring, the ring is preferably an azetidine ring,pyrrolidine ring, piperidine ring or piperazine ring. The substituentsof the ring are preferably lower alkyl groups, halogen atoms, arylgroups, substituted aryl groups, hydroxyl groups and substituted orunsubstituted amino groups. The substituents of the aryl groups arepreferably hydrogen atoms, halogen atoms, hydroxyl groups, lower alkylgroups, lower alkoxyl groups, halogeno-lower alkyl groups andhalogeno-lower alkoxyl groups. The substituents of the amino group arepreferably lower alkyl groups and lower alkanoyl groups.

[0053] It is preferred that in general formula (1) in the presentinvention, X represents an interatomic bond or a group of the formula:—O—, —O—SO₂—, —NR¹—, —NR¹—C(═O)—, —NR¹—SO₂— or —C(═O)—, Y represents agroup of the formula: —C(═O)—, Z represents a group of —C(═O)— or—O—SO₂—, A represents a group of general formula (2), a group of any ofgeneral formulae (2-1) to (2-5), a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with a group of general formula (2), a lower alkyl groupsubstituted with an aryl group(s) or a lower alkyl group substitutedwith a heteroaryl group(s), B represents hydroxyl group or a loweralkoxyl group, C represents hydrogen atom or a lower alkyl group, D andE may be the same or different and each represent a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with an aryl group(s), a lower alkenyl group substitutedwith a heteroaryl group(s), a halogeno-lower alkyl group, a loweralkoxy-lower alkyl group, a hydroxy-lower alkyl group, a loweralkylthio-lower alkyl group, a mercapto-lower alkyl group or asubstituted or unsubstituted amino-lower alkyl group, or D and E may bebonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms, and n represents an integer of 0.

[0054] It is preferred that in general formula (1) in the presentinvention, X represents an interatomic bond or a group of the formula:—O—, —O—SO₂—, —NR¹—, —NR¹—C(═O)—, —NR¹—SO₂—, —NR¹—C(═O)—NH— or—NR¹—C(═S)—NH—, wherein R¹ represents a hydrogen atom, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s) or a lower alkyl group substituted with a heteroarylgroup(s),

[0055] Y represents any of —C(═O)—, —S(═O)— or —O—SO₂—,

[0056] Z represents any of group of —C(═O)—, —S(═O)— or —SO₂—,

[0057] A represents a group of general formula (2), a lower alkyl group,a lower alkenyl group, a lower alkynyl group, a cycloalkyl group whichmay contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with a group of general formula (2), a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s) or a lower alkynyl groupsubstituted with a heteroaryl group(s).

[0058] R², R³, R⁴, R⁵ and R⁶ in general formula (2) may be the same ordifferent from one another, and each represents a hydrogen atom, ahalogen atom, a hydroxyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with an aryl group(s), a lower alkyl group substituted witha heteroaryl group(s), a lower alkoxyl group, a lower alkoxyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkoxyl group substituted with anaryl group(s), a lower alkoxyl group substituted with a heteroarylgroup(s), a cycloalkyloxy group which may contain a hetero atom(s) inthe ring thereof, an aryloxy group, a heteroaryloxy group, ahydroxy-lower alkyl group, a hydroxy-lower alkenyl group, ahydroxy-lower alkoxyl group, a halogeno-lower alkyl group, ahalogeno-lower alkoxyl group, a halogeno-lower alkenyl group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkanoyl group, an aroyl group, a loweralkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group:

[0059] B represents hydroxyl group, a lower alkoxyl group orhydroxyamino group,

[0060] C represents a hydrogen atom, a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a lower alkyl group substitutedwith a cycloalkyl group(s) which may contain a hetero atom(s) in thering thereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s),

[0061] D and E may be the same or different from each other and eachrepresents a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group or a hydroxy-lower alkyl group,or D and E may be bonded together to form a ring which may contain oneor two oxygen, nitrogen or sulfur atoms,

[0062] F and G may be the same or different from each other and eachrepresents a hydrogen atom, a lower alkyl group, a lower alkenyl group,a lower alkynyl group, a cycloalkyl group which may contain a heteroatom(s) in the ring thereof, an aryl group, a heteroaryl group, a loweralkyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkyl group substituted withan aryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group or a hydroxy-lower alkyl group,or F and G may be bonded together to form a ring which may contain oneor two oxygen, nitrogen or sulfur atoms,

[0063] n represents an integer of 0 to 2,

[0064] K represents OR⁷, NR⁷R⁸, NHNR⁷R⁸, NR⁷NHR⁸, SR⁷ or R⁷ wherein R⁷and R⁸ may be the same or different from each other and each representsa hydrogen atom, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group, a halogeno-lower alkenyl group,a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group or asubstituted or unsubstituted amino-lower alkyl group, or R⁷ and R⁸ maybe bonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms; and the substituents of the ring include ahydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and

[0065] J and J′ may be the same or different from each other and eachrepresents a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkyloxy group or nitro group.

[0066] It is preferred that in general formula (1), X represents a groupof the formula: —O—, Y represents a group of the formula: —C(═O)—, Zrepresents a group of the formula: —C(═O)—, A represents a lower alkylgroup substituted with a group of general formula (2), R², R³, R⁴, R⁵and R⁶ may be the same or different from one another, and each representa hydrogen atom or a halogen atom, B represents a hydroxyl group, Crepresents a hydrogen atom, D and E may be the same or different fromeach other and each represents a lower alkyl group, or D and E may bebonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms, n represents an integer of 0, K representsNR⁷R⁸ or NHNR⁷R⁸, R⁷ and R⁸ may be the same or different from each otherand each represents a hydrogen atom, a lower alkyl group, a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, an arylgroup, a heteroaryl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s) or R⁷ and R⁸may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms; and the substituents of the ringinclude a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a cycloalkyl groupwhich may contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and

[0067] J and J′ each represents hydrogen atom.

[0068] It is preferred that in general formula (1),

[0069] X represents a group of the formula: —NR¹—C(═O)—,

[0070] Y represents a group of the formula: —C(═O)—,

[0071] Z represents a group of the formula: —C(═O)—,

[0072] A represents a group of general formula (2) wherein R², R³, R¹,R⁵ and R⁶ may be the same or different from one another, and eachrepresent a hydrogen atom or a halogen atom, a cycloalkyl group whichmay contain a hetero atom(s) in the ring thereof or a heteroaryl group,

[0073] B represents a hydroxyl group,

[0074] C represents a hydrogen atom,

[0075] D and E may be the same or different from each other and eachrepresents a lower alkyl group, or D and E may be bonded together toform a ring which may contain one or two oxygen, nitrogen or sulfuratoms,

[0076] n represents an integer of 0,

[0077] K represents NR⁷R⁸ or NHNR⁷R⁸,

[0078] R⁷ and R⁸ may be the same or different from each other and eachrepresents a hydrogen atom, a lower alkyl group, a cycloalkyl groupwhich may contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s) or a lower alkyl groupsubstituted with a heteroaryl group(s) or R⁷ and R⁸ may be bondedtogether to form a ring which may contain one or two oxygen, nitrogen orsulfur atoms; and the substituents of the ring include a hydrogen atom,a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with an aryl group(s), a lower alkyl group substituted witha heteroaryl group(s), a lower alkanoyl group, an aroyl group, ahalogeno-lower alkanoyl group, a lower alkyloxy group, nitro group,cyano group, a substituted or unsubstituted amino group, carboxyl group,a lower alkyloxycarbonyl group, a substituted or unsubstituted carbamoylgroup, a lower alkylthio group, a lower alkylsulfonyl group or asubstituted or unsubstituted sulfamoyl group, and

[0079] J and J′ each represent a hydrogen atom.

[0080] It is preferred that in general formula (1),

[0081] X represents an interatomic bond,

[0082] Y represents a group of the formula: —C(═O)—,

[0083] Z represents a group of the formula: —C(═O)—,

[0084] A represents a cycloalkyl group which may contain a heteroatom(s) in the ring thereof or a heteroaryl group,

[0085] B represents a hydroxyl group,

[0086] C represents a hydrogen atom,

[0087] D and E may be the same or different from each other and eachrepresents a lower alkyl group, or D and E may be bonded together toform a ring which may contain one or two oxygen, nitrogen or sulfuratoms,

[0088] n represents an integer of 0,

[0089] K represents NR⁷R⁸,

[0090] R⁷ and R⁸ may be the same or different from each other and eachrepresents a hydrogen atom, a lower alkyl group, a cycloalkyl groupwhich may contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s) or a lower alkyl groupsubstituted with a heteroaryl group(s) or R⁷ and R⁸ may be bondedtogether to form a ring which may contain one or two oxygen, nitrogen orsulfur atoms; and the substituents of the ring include a hydrogen atom,a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with an aryl group(s), a lower alkyl group substituted witha heteroaryl group(s), a lower alkanoyl group, an aroyl group, ahalogeno-lower alkanoyl group, a lower alkyloxy group, nitro group,cyano group, a substituted or unsubstituted amino group, carboxyl group,a lower alkyloxycarbonyl group, a substituted or unsubstituted carbamoylgroup, a lower alkylthio group, a lower alkylsulfonyl group or asubstituted or unsubstituted sulfamoyl group, and

[0091] J and J′ and each represent a hydrogen atom.

[0092] A is preferably a cycloalkyl group containing a hetero atom(s) inthe ring thereof, which is represented by any of formulae (2-1) to(2-5).

[0093] The following compounds and pharmaceutically acceptable saltsthereof are preferred:

[0094]N-[2-(N,N-dimethylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0095]N-[2-(N,N-diethylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0096]N-[2-(N,N-dimethylaminocarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0097]N-[2-(N,N-diethylaminocarbonyl)-2-methyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0098]N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0099]N-[1-(N,N-diethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0100]N-[2-(piperidine-1-ylcarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0101]N-[2-(piperidine-1-ylcarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0102]N-[1-(piperidine-1-ylcarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0103]N-[2-(N-methyl-N-phenylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0104]N-[2-(N-methyl-N-phenylaminocarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0105]N-[1-(N-methyl-N-phenylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0106]N-[2-(4-hydroxyphenylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0107]N-[2-(4-hydroxyphenylaminocarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0108]N-[1-(4-hydroxyphenylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0109]N-{2-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-methyl-propanoyl}-O-(2,6-di-chlorobenzyl)-L-tyrosine;

[0110]N-{2-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-ethyl-butanoyl}-O-(2,6-dichlorobenzyl)-L-tyrosine;and

[0111]N-{1-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-ethyl-butanoyl}-O-(2,6-dichlorobenzyl)-L-tyrosine;

[0112] The following compounds and pharmaceutically acceptable salts ofthem are preferred

[0113] The following compounds and pharmaceutically acceptable salts ofthem are also preferred in the present invention.

[0114] The phenylalanine derivatives (1) of the present invention can besynthesized by methods described below. For example, a phenylalaninederivative (9) of general formula (1) wherein —X—A represents a groupdefined by Q described below, Y represents a group of the formula:—C(═O)—, Z represents a group of the formula: —C(═O)—, B representshydroxyl group and C represents hydrogen atom is synthesized as follows:

[0115] A suitably protected carboxylic acid (3) is introduced into aresin by a usual method. The substituent Q of the carboxylic acid (3)has a structure of —X—A as described above with reference to the generalformula (1), it is a substituent which can be converted into —X—A in anystage of the synthesis or it is suitably protected form of thesesubstituents. As for the introduction reaction conditions, the reactioncan be conducted by using, if necessary, a suitable additive such asHOAt (1-hydroxy-7-azabenzotriazole) or HOBt (1-hydroxybenzotriazole) anda condensing agent such as DIC (diisopropylcarbodiimide), DCC(dicyclohexylcarbodiimide) or EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) in an organic solventsuch as dichloromethane, DMF (N,N-dimethylformamide) or NMP(N-methyl-2-pyrrolidone). For example, when Wang resin is used, thereaction is carried out in the presence of pyridine and2,6-dichlorobenzoyl chloride in DMF to obtain an ester (4). Theprotective group P1 is removed from the ester (4) under suitableconditions to obtain an amine (5). For example, when Fmoc group(9-fluorenylmethoxycarbonyl group) is used as P1, the protective groupcan be removed with a base such as piperidine in a solvent such as DMF.The amine (5) can be converted into a carboxylic acid (6) by condensingit with a suitable dicarboxylic acid by using a condensing agent such asDIC and, if necessary, a suitable additive such as HOAt or HOBt in anorganic solvent such as DMF, NMP or dichloromethane. The carboxylic acid(6) can be converted into a carbonyl derivative (7) by reacting it withan amine, an alcohol, a hydrazine or a thiol under the same conditionsas those in the above-described condensation reaction.

[0116] The amine (5) can be converted into a carbonyl derivative (8) byreacting it with a carboxylic acid (10), synthesized by a methoddescribed hereafter, under the above-described condensation reactionconditions.

[0117] The carbonyl derivative (7) or the carbonyl derivative (8)obtained as described above is cleaved from the resin under suitableconditions to obtain a carboxylic acid (9). For example, when Wang resinis used as the resin, the product is treated with an acidic reactionsolution containing, for example, TFA (trifluoroacetic acid) to obtain acarboxylic acid (9) solution and then the solvent is evaporated toobtain a carboxylic acid (9). The carboxylic acid (9) thus obtained ispurified by the column chromatography, HPLC, recrystallization or thelike to obtain a pure carboxylic acid (9).

[0118] The compounds of the general formula (1) can be synthesized alsoby the following method:

[0119] A suitably protected amine (11) is reacted with a carboxylic acid(10), synthesized by a method described hereafter, by using, ifnecessary, a suitable additive such as HOAt or HOBt and a condensingagent such as DIC, DCC or EDC in an organic solvent such asdichloromethane, DMF or NMP to obtain a carbonyl derivative (12). Thesubstituent Q of the amine (11) has a structure of —X—A as describedabove with reference to the general formula (1), or it is a substituentwhich can be converted into —X—A in any stage of the synthesis or thesubstituent which is suitably protected. The protective group is removedfrom thus obtained carbonyl derivative (12) under suitable conditions toobtain the carboxylic acid (9). For example, the protective group can beremoved by the alkali hydrolysis when P² is methyl or ethyl group, or bythe treatment with an acidic solution when P² is t-butyl group or by thehydrolysis followed by the reaction with hydrogen in the presence of ametal catalyst when P² is benzyl group or the like.

[0120] The carboxylic acid (10) can be synthesized by the followingmethod:

[0121] Namely, a disubstituted malonic acid (13) is reacted with asuitable amount of an amine, an alcohol, a hydrazine or a thiol by usinga suitable condensing agent such as DIC, DCC or EDC in the presence of asuitable additive in a suitable organic solvent such as dichloromethaneor DMF and then the product is purified by a suitable method such asrecrystallization to obtain the carboxylic acid (10).

[0122] A monocarboxylic acid (15) can be obtained by esterifying themalonic acid (13) by an ordinary method to form a diester (14) and thenreacting the diester (14) with a suitable amount of a base such assodium hydroxide, potassium hydroxide or lithium hydroxide in an organicsolvent such as methanol, ethanol or THF or in a mixed solvent of theorganic solvent with water. The monocarboxylic acid (15) is reacted withsuitable amount of an amine, an alcohol, a hydrazine or a thiol by usinga suitable condensing agent such as DIC, DCC or EDC in the presence of asuitable additive in a suitable solvent such as dichloromethane or DMFto obtain a carbonyl derivative (16) and then this product is hydrolyzedunder the same reaction conditions as those described above to obtainthe carboxylic acid (10).

[0123] The diester (14) can be obtained also by reacting a malonicdiester (17) with an alkylating agent such as an alkyl halide or analkyl sulfonate in the presence of a base such as a metal alkoxide orLDA in a solvent such as an alcohol, THF or an ether. It is alsopossible to obtain the diester (14) of the above formula wherein D isdifferent from E by controlling the amount of the reagents andconducting the reaction in two steps:

[0124] When the group represented by K—Z is an acyl group and the grouprepresented by Z is —S—, —S(═O)— or —SO₂—, an ester (19) can be obtainedfrom a corresponding ester (18) under the same reaction conditions asthose in the production of the diester (14) from the malonic diester(17). When the group represented by Z in the ester (19) is —S—, thisgroup can be converted to —S(═O)— or —SO₂— by oxidization. The ester(19) can be converted to a carboxylic acid (10a) under theabove-described hydrolysis conditions. It is also possible to synthesizea compound of the general formula (1) wherein Z represents —S—, —S(═O)—or —SO₂— by using a carboxylic acid (10a) by the same reaction as thatfor obtaining the carbonyl derivative (8) from the amine (5).

[0125] Various partial structures of —X—A in the general formula (1) canbe synthesized from corresponding precursors by reactions describedbelow. By the reactions described below, Q in the precursor structurecan be converted into —X—A in a suitable stage in an ordinary method forsynthesizing the compounds of the general formula (1).

[0126] When Q is hydroxyl group or a suitably protected hydroxyl group,the protective group is removed, if necessary, to form hydroxyl groupand then the subsequent conversion reaction can be conducted asdescribed below.

[0127] Hydroxyl group Q can be reacted with an alkylating agent such asan alkyl halide or an alkyl sulfonate in the presence of a suitable basein an organic solvent to form various ether-type structures. Theether-type compounds can be formed also by subjecting the obtainedcompound to Mitsunobu reaction with an alcohol in the presence of adialkylazodicarboxylic acid. The compounds having structures of variousaryl ether types or heteroaryl ether types can be formed by reacting theobtained compound with an aryl halide, a heteroaryl halide, anarylboronic acid or a heteroarylboronic acid in the presence of asuitable base or catalyst in an organic solvent.

[0128] Hydroxyl group Q can be reacted with a sulfonic acid halide orsulfonic acid anhydride in the presence of an organic base such astriethylamine, diisopropylethylamine, pyridine orN,N-dimethylaminopyridine or an inorganic base such as potassiumcarbonate or sodium carbonate in an organic solvent such as DMF ordichloromethane to form a corresponding product having a sulfonic acidester structure.

[0129] A trifluoromethanesulfonic acid ester (hereinafter referred to as“triflate” can be obtained under the above-described sulfonationreaction conditions. The triflate can be converted into anaryl-substituted compound or a heteroaryl-substituted compound by Suzukicoupling reaction wherein it is reacted with a various boric acid in thepresence of a palladium catalyst such as tetrakistriphenylphosphinepalladium or palladium acetate or another metal catalyst in a solventsuch as DMF DME (1,2-dimethoxylethane), toluene or dioxane at roomtemperature or an elevated temperature. The conversion reaction into thearyl-substituted compounds can be carried out by using not only thetriflate but also a compound of the above formula wherein Q issubstituted with a halogen atom.

[0130] When Q is a properly protected amino group, the protective groupcan be removed to form the amino group by a method suitably selecteddepending on the protective group. When Q is nitro group, it can beconverted into the amino group by the hydrogenation reaction in thepresence of a metal catalyst or by the reduction reaction with areducing agent selected from among various reducing agents. The aminogroup thus obtained can be further converted into groups of variousstructures by various reactions described below.

[0131] The amino group can be further converted into an alkylamino groupby reacting it with an alkylating agent such as an alkyl halide or analkyl sulfonate in the presence of a suitable base in an organicsolvent. Various arylamine structures can be formed by reacting theamino group with an aryl halide in the presence of a suitable base in anorganic solvent.

[0132] The amino group can be converted into an alkylamino group byreacting it with an aldehyde or a ketone in the presence of a reducingagent such as sodium borohydride or sodium cyanoborohydride in a solventsuch as DMF, dichloromethane, a trialkylorthoformic acid or atrialkylorthoacetic acid. The amino group or alkylamino group can beconverted into groups of various structures by reactions describedbelow.

[0133] The amino group or alkylamino group can be converted into acorresponding structure of amide type or sulfonamide type by reacting itwith a carboxylic acid halide, a carboxylic acid anhydride, a sulfonicacid halide or a sulfonic acid anhydride in the presence of an organicbase such as triethylamine, diisopropylethylamine, pyridine orN,N-dimethylaminopyridine or an inorganic base such as potassiumcarbonate or sodium carbonate in an organic solvent such as DMF ordichloromethane. The amino group or alkylamino group can be convertedinto a corresponding structure of amide type also by reacting it with acarboxylic acid in the presence of a suitable additive and condensingagent in an organic solvent such as DMF or dichloromethane.

[0134] The amino group or alkylamino group can be converted into acorresponding structure of urea type or thiourea type by reacting itwith an isocyanate or an isothiocyanate in the presence of, ifnecessary, an organic base such as triethylamine, diisopropylethylamine,pyridine or N,N-dimethylaminopyridine in an organic solvent such as DMF,toluene or dichloromethane.

[0135] The amino group can be converted into a corresponding structureof amide type by reacting it with a properly protected aminocarboxylicacid in the presence of suitable additive and condensing agent in asuitable organic solvent such as DMF or dichloromethane or by reactingit with a properly protected aminocarboxylic acid halide in the presenceof a suitable base. After removing the protective group, the obtainedcompound can be reacted with 1,1-carbonyldiimidazole or trimethylo-formate to obtain the ring-closed compound. The ring-closed compoundcan be converted into an N-alkylated ring-closed compound by alkylatingit under suitable conditions.

[0136] The product having the sulfonamide structure formed as describedabove can be alkylated by the above-described Mitsunobu reaction with analcohol. The alkylation reaction can be carried out also by reacting thecompound with an alkylating agent such as an alkyl halide or an alkylsulfonate in the presence of a suitable base in an organic solvent. Whenan isocyanate or isothiocyanate having a leaving group at a properposition is used in the formation of the product having the urea-type orthiourea-type structure, a ring-closed compound can be obtained bytreating the formed urea-type or thiourea-type compound with a base orthe like. The compound can be further N-alkylated under suitableconditions.

[0137] Optical isomers of the phenylalanine derivatives represented bythe general formula (1) in the present invention are possible becausethey have an asymmetric carbon atom. The compounds of the presentinvention also include those optical isomers. When the compounds havediastereomers, the diastereomers and a diastereomer mixture are alsoincluded in the present invention. Various tautomers of thephenylalanine derivatives of the general formula (1) are possible in thepresent invention because they contain exchangeable hydrogen atoms. Thecompounds of the present invention also include those tautomers. Thecarboxyl group in the compounds of the present invention may besubstituted with a substituent which can be converted to form thecarboxyl group in vivo.

[0138] When the compounds of general formula (1) can form salts thereof,the salts are pharmaceutically acceptable ones. When the compound has anacidic group such as carboxyl group, the salts can be ammonium salts, orsalts thereof with alkali metals, e.g. sodium and potassium, saltsthereof with alkaline earth metals, e.g. calcium and magnesium, saltsthereof with aluminum and zinc, salts thereof with organic amines, e.g.triethylamine, ethanolamine, morpholine, piperidine anddicyclohexylamine, and salts thereof with basic amino acids, e.g.arginine and lysine. When the compound has a basic group, the salts canbe those with inorganic acids, e.g. hydrochloric acid, sulfuric acid andphosphoric acid; those with organic acids, e.g. acetic acid, citricacid, benzoic acid, maleic acid, fumaric acid, tartaric acid andsuccinic acid; and those with organosulfonic acids, e.g. methanesulfonicacid and p-toluenesulfonic acid. The salts can be formed by mixing acompound of the general formula (1) with a necessitated acid or base ina proper ratio in a solvent or dispersing agent or by the cationexchange or anion exchange reaction with another salt.

[0139] The compounds of the general formula (1) of the present inventioninclude also solvates thereof such as hydrates and alcohol adductsthereof.

[0140] The compounds of general formula (1) and salts thereof areadministered as they are or in the form of various medicinalcompositions to patients. The dosage forms of the medicinal compositionsare, for example, tablets, powders, pills, granules, capsules,suppositories, solutions, sugar-coated tablets, depots and syrups. Theycan be prepared with ordinary preparation assistants by an ordinarymethod.

[0141] For example, the tablets are prepared by mixing the phenylalaninederivative, the active ingredient of the present invention, with any ofknown adjuvants such as inert diluents, e.g. lactose, calcium carbonateand calcium phosphate; binders, e.g. acacia, corn starch and gelatin;extending agents, e.g. alginic acid, corn starch and pre-gelatinizedstarch; sweetening agents, e.g. sucrose, lactose and saccharin;corrigents, e.g. peppermint, Akmono (Gaultheria aderothrix) Oil andcherry; lubricants, e.g. magnesium stearate, talc and carboxymethylcellulose; excipients for soft gelatin capsules and suppositories, e.g.fats, waxes, semi-solid or liquid polyols, natural oils and hardenedoils; and excipients for solutions, e.g. water, alcohols, glycerols,polyols, sucrose, invert sugars, glucose and vegetable oils.

[0142] The antagonist containing one of the compounds of above generalformula (1) or one of salts thereof as active ingredient is usable as atherapeutic agent or preventing agent for diseases in which a 4integrin-depending adhesion process participates in the pathology, suchas inflammatory diseases, rheumatoid arthritis, inflammatory boweldiseases, systemic erythematodes, multiple sclerosis, Sjogren'ssyndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases,arterial sclerosis, restenosis, tumor proliferation, tumor metastasis,transplantation rejection, etc.

[0143] The dose of the compound of general formula (1) or salt thereofused for the above-described purpose varies depending on the intendedtherapeutic effect, administration method, period of the treatment, andage and body weight of the patient. The dose is usually 1 μg to 5 g aday for adults in the oral administration, and 0.01 μg to 1 g a day foradults in the parenteral administration.

[0144] The following Examples will further illustrate the presentinvention, which are only preferred embodiments of the invention andwhich by no means limit the invention.

EXAMPLE 1 Preparation of Resin

[0145] 3.0 g of Wang resin (0.87 mmol/g) was suspended in DMF, and theobtained suspension was left to stand at room temperature for 3 hours.The superfluous solvent was removed, and the rest was added to asolution of 4.4 g of Fmoc-Tyr-(2,6-dichlorobenzyl)-OH, 1.2 ml of2,6-dichlorobenzoyl chloride and 1.2 ml of pyridine in 30 ml of DMF, andthe resultant mixture was shaken at room temperature for 20 hours. Thesuperfluous solvent was removed, and the resin was washed with 30 ml ofDMF twice. The obtained resin was treated with 20% solution ofpiperidine in DMF at room temperature for 3 hours. The solvent wasremoved, and the residue was washed with 30 ml of each of DMF anddichloromethane 3 times. The obtained resin was used for the subsequentreaction.

EXAMPLE 2 Synthesis ofN-[2-(dimethylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine

[0146] 30 mg of the resin obtained in Example 1 was added to a solutionof 160 mg of dimethylmalonic acid, 140 mg of HOAt, 150 μl of DIC and 1.5ml of DMF to conduct the reaction at room temperature for 20 hours. Thesolution was removed and the remaining resin was washed with DMF twiceand added to a mixture of 0.5 ml of 2M dimethylamine solution in THF,140 mg of HOAt and 150 μl of DIC in 1.0 ml of DMF and reacted for 20hours. The reaction solution was removed, and the resin was washed withDMF, dichloromethane and ether 3 times each. The resin was treated with95% aqueous trifluoroacetic acid solution for 1 hour. The resin wasremoved by the filtration and then washed with acetonitrile. The washsolutions were combined together, concentrated and purified by thereversed-phase HPLC [Inertsil ODS column, developer: water/acetonitrile(TFA 0.05%)] to obtain 4.3 mg of the intended compound.

[0147] MS (ESI positive): 481, 483, 485

[0148] [C₂₃H₂₆N₂O₅Cl₂: 480, 482, 484]

EXAMPLES 3 TO 9, 32-78, 80, 84, 450-457 AND 459 TO 475

[0149] The same procedure as that of Example 2 was repeated except thatthe resin prepared in Example 1 and a dicarboxylic acid and an aminewere used to obtain the compounds shown in Table 1.

EXAMPLES 10 TO 31

[0150] The same procedure as that of Example 2 was repeated except thatthe resin prepared in Example 1 and a dicarboxylic acid and an aminewere used and that HPLC purification was omitted to obtain the compoundsshown in Table 2.

[0151] D, E and K in Tables 1 and 2 are substituents in general formula(1-1) given below.

EXAMPLE 79 Synthesis ofN-(2-{[(trans-3,4-dibromopyrrolidine)-1-yl]carbonyl}-2-ethyl-butanoyl)-O-(2,6-dichlorobenzyl)-L-tyrosine

[0152] 20 mg of a resin obtained in step 1 in Example 83 which will bedescribed below was reacted with 600 mg of tetrabutylammonium tribromideand 2 ml of DCM for 4 days, and the reaction product was washed with DMFand DCM 3 times each and then dried under reduced pressure. Aftertreating the resin with 1.5 ml of 95% aqueous trifluoroacetic acidsolution for 1 hour, the filtrate was concentrated under reducedpressure and then purified by the reversed-phase HPLC [Inertsil ODScolumn, developer: water/acetonitrile (TFA 0.05%)] to obtain 10 mg ofthe intended compound.

[0153] MS (ESI positive): 691, 693, 695

[0154] C₂₇H₁₀Br₂Cl₂N₂O₅: 690, 692, 694

EXAMPLE 81 Synthesis ofN-(2-{[(cis-3,4-dihydroxypyrrolidine)-1-yl]carbonyl}-2-ethyl-butanoyl)-O-(2,6-dichlorobenzyl)-L-tyrosine

[0155] 20 mg of the resin obtained in step 1 in Example 83 was reactedwith 40 mg of OsO₄ and 2 ml of dioxane for 16 hours, and then washedwith each of DMF, DCM and DMF repeatedly 3 times. The resin was treatedwith a solution of 0.2 g of NaHSO₃ in a mixed solvent of water (1 ml)and methanol (1 ml), then washed with each of H₂O, MeOH, DMF and DCMrepeatedly 3 times and then dried under reduced pressure. After treatingthe product with 1.5 ml of trifluoroacetic acid containing 5% of waterfor 1 hour, the filtrate was concentrated under reduced pressure andthen purified by the reversed-phase HPLC [Inertsil ODS column,developer: water/acetonitrile (TFA 0.05%)] to obtain 0.9 mg of theintended compound.

[0156] MS (ESI positive): 567

[0157] C₂₇H₃₂Cl₂N₂O₇: 566

EXAMPLE 82 Synthesis ofN-(2-{[(trans-3-hydroxy-4-chloropyrrolidine)-1-yl]carbonyl})-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine:

[0158] 1 M solution (1.5 ml) of HCl in dioxane was added to 10 mg of theresin obtained in step 2 in Example 83, and they were reacted for 1hour. The filtrate was concentrated under reduced pressure and thenpurified by the reversed-phase HPLC [Inertsil ODS column, developer:water/acetonitrile (TFA 0.05%)] to obtain 0.9 mg of the intendedcompound.

[0159] MS (ESI positive): 585

[0160] C₂₇H₃₁Cl₃N₂O₆: 584

EXAMPLE 83 Synthesis ofN-(2-{[(trans-3,4-dihydroxypyrrolidine)-1-yl]carbonyl}-2-ethyl-butanoyl)-O-(2,6-dichlorobenzyl)-L-tyrosine

[0161] Step 1 Preparation of Resin:

[0162] 1.5 g of the resin (H-Tyr(2,6-dichlorobenzyl)-O-Wang) obtained bythe method of Example 1 was added to a solution of 2.9 g ofdiethylmalonic acid, 7.45 g of HOAt, 8.4 ml of DIC and 24 ml of NMP toconduct the reaction at room temperature for 16 hours. The reactionsolution was removed, and the resin was washed with DMF 5 times. Aftercarrying out the reaction in a solution of 766 μl of pyrroline, 1.37 gof HOAt and 1.5 ml of DIC in 15 ml of NMP for 16 hours, the reactionsolution was removed, and the resin was washed with each of DMF and DCMrepeatedly 3 times and then dried under reduced pressure.

[0163] Step 2 Oxidation of Double Bond:

[0164] 20 mg of the resin obtained in step 1 was washed with DCM 3 timesand then reacted with 698 mg of mCPBA for 4 days. The reaction solutionwas removed, and the resin was washed with DCM 5 times and then driedunder reduced pressure.

[0165] Step 3 Removal of Resin:

[0166] The resin obtained in step 2 was treated with 1.5 ml of 95%aqueous trifluoroacetic acid solution for 1 hour. The filtrate wasconcentrated under reduced pressure and then purified by thereversed-phase HPLC [Inertsil ODS column, developer: water/acetonitrile(TFA 0.05%)] to obtain 7.0 mg of the intended compound.

[0167] MS (ESI positive): 567

[0168] C₂₇H₁₂Cl₁₂N₂O₇: 566 TABLE 1

Example D E K MS Found (MH+) 3 Et Et Me2N 509, 511, 513 4 Et Et PhNH557, 559, 561 5 Et Et (4-HOPh)NH 573, 575, 577 6 Et Et (4-HOPh)CH2CH2NH601, 603, 605 7 Et Et (4-HOPh)piperazino 642, 644, 646 8 —(CH2)4— Me2N507, 509, 511 9 —(CH2)4— (4-HOPh)piperazino 640, 642, 644 32 Et EtPyrrolidino 535, 537, 539 33 Me Me Pyrrolidino 507, 509, 511 34 Et EtMorpholino 551, 553, 555 35 Et Et (R)-3-Hydroxypyrrolidino 551, 553, 55536 Et Et Thiomorpholino 567, 569, 571 37 Et nPr Pyrrolidino 549, 551,553 38 Me Et Pyrrolidino 521, 523, 525 39 Et Et4-(Aminocarbonyl)piperidino 592, 594, 596 40 Et Et Me2NCH2CH2NMe 566,568, 570 41 Et Et EtMeN 523, 525, 527 42 Et Et Homopiperazino 564, 566,568 43 Et MeOCH2CH2 Pyrrolidino 565, 567, 569 44 Et Et(R)-3-Dimethylaminopyrrolidino 578, 580, 582 45 Et Et 4-Formylpiperazino578, 580, 582 46 Et Et (2S,4R)-4-Hydroxy-2-methoxy- 609, 611, 613carbonylpyrrolidino 47 Et Et (R,S)-3-Aminopyrrolidino 550, 552, 554 48Et Et (R,S)-3-Hydroxypiperidino 565, 567, 569 49 Et Et(R,S)-4-Hydroxypiperidino 565, 567, 569 50 Et Et(S)-2-(Methoxymethyl)pyrrolidino 579, 581, 583 51 Et Et(R,S)-2-(Aminocarbonyl)piperidino 591, 593, 595 52 Et Et partialstructure 1 562, 564, 56 53 Et Et (S)-2-(Pyrrolidinomethyl)-pyrrolidino618, 620, 622 54 Et Et (R)-3-(Acetylamino)pyrrolidino 592, 594, 596 55Et Et (S)-3-(Acetylamino)pyrrolidino 592, 594, 596 56 Et Et(R)-2-(Methoxycarbonyl)pyrrolidino 593, 595, 597 57 Et Et[3(R,S),5(R,S)]-3,5-Dimethylmorpholino 579, 581, 583 58—(CH2)2—O—(CH2)2— Pyrrolidino 549, 551, 553 59 —(CH2)2— 3-Oxopyrrolidino519, 521, 523 60 Et Et (R,S)-3-(Hydroxymethyl)piperidino 79, 581, 583 61Et Et 4-Formylhomopiperazino 592, 594, 596 62 Et Et partial structure 2533, 536, 537 63 Et Et (R)-3-(Trifluoromethylcarbonyl- 646, 648, 650amino)pyrrolidino 64 Et Et (R)-3-(Methylamino)pyrrolidino 564, 566, 56865 Et Et (S)-3-Hydroxypyrrolidino 551, 553, 555 66 Et Et(S)-3-Aminopyrrolidino 550, 552, 554 67 Et Et(S)-2-(Aminocarbonyl)pyrrolidino 578, 580, 582 68 Et Et(2R,4R)-4-Hydroxy-2-methoxy- 609, 611, 613 carbonylpyrrolidino 69 Et Et3-Oxopyrrolidino 549, 551, 553 70 Et Et (R)-2-(Aminocarbonyl)pyrrolidino578, 580, 582 71 Et Et (2R,4R)-2-Aminocarbonyl-4- 594, 596, 598hydroxypyrrolidino 72 Et Et (S)-2-(Methylaminocarbonyl)-pyrrolidino 592,594, 596 73 Et Et (2S,4R)-2-Aminocarbonyl-4- 594, 596, 598hydroxypyrrolidino 74 Et Et partial structure 3 563, 565, 567 75 Et Etpartial structure 4 579, 581, 583 76 Et Et (R)-3-Aminopyrrolidino 550,552, 554 77 Et Et (R)-3-Hydroxypiperidino 565, 567, 569 78 Et EtAzetidino 521, 523, 525 79 Et Et trans-3,4-Dibromopyrrolidino 691, 693,695 80 Et Et (S)-3-Fluoropyrrolidino 553, 555, 557 81 Et Etcis-3,4-Dihydroxypyrrolidino 567 82 Et Ettrans-3-Chloro-4-hydroxypyrrolidino 585 83 Et Ettrans-3,4-Dihydroxypyrrolidino 567 84 Et Et (R)-3-Fluoropyrrolidino 553,555, 557 450 Et 3-Methylbutyl Pyrrolidino 577, 579, 581 451 Allyl AllylPyrrolidino 559, 561, 563 452 Et Benzyl Pyrrolidino 597, 599, 601 453 EtCyclopentyl Pyrrolidino 575, 577, 579 454 Et Butyl Pyrrolidin 563, 565,567 455 nPr MeOCH2CH Pyrrolidino 579, 581, 583 456 Me MeOCH2CH2Pyrrolidino 551, 553, 555 457 Butyl MeOCH2CH2 Pyrrolidino 593, 595, 597459 Et Et (R)-2-(Benzyloxycarbonyl)pyrrolidino 669 460 Et Et(S)-2-(Dimethylaminocarbonyl)pyrrolidino 606 461 —(CH₂)₃— partialstructure 4-1 565 462 —(CH₂)₃— partial structure 4-2 641 463 —(CH₂)₃—4-Formylpiperazino 562 464 Et Et 4-Acetylpiperazino 592 465 Et Et4-Formylhomopiperazino 606 466 Et Et partial structure 4-3 604 467—(CH₂)₂—O—(CH₂)₂— (R)-3-Hydroxypyrrolidino 565 468 —(CH₂)₂O—(CH₂)₂— Me2N523 469 —(CH₂)₂O—(CH₂)₂— partial structure 4-4 611 470 —(CH₂)₂—O—(CH₂)₂—partial structure 4-5 631 471 —(CH₂)₂—O—(CH₂)₂— partial structure 4-6631 472 —(CH₂)₂—O—(CH₂)₂— partial structure 4-7 631 473—(CH₂)₂—O—(CH₂)₂— partial structure 4-8 643 474 —(CH₂)₂—O—(CH₂)₂—partial structure 4-9 629 475 —(CH₂)₂—O—(CH₂)₂— partial structure 4-10669

[0169] In the table, 4-HOPh represents 4-hydroxyphenyl (the same shallapply hereinafter).

Partial Structures

[0170] TABLE 2

1

2

3

4

4-1

4-2

4-3

4-4

4-5

4-6

4-7

4-8

4-9

4-10 Example D B K MS Found (MH+) 10 Me Me nBuNH 509, 511, 513 11 Me MeiBuNH 509, 511, 513 12 Me Me BnNH 543, 545, 547 13 Me Me PhNH 529, 531,533 14 Me Me (4-HOPh) NH 545, 547, 549 15 Et Et cHexNH 563, 565, 567 16Et Et BnNH 571, 573, 575 17 Et Et 1-Piperidino 549, 551, 553 18 —(CH2)2—iBuNH 507, 509, 511 19 —(CH2)2— tBuNH 507, 509, 511 20 —(CH2)2— BnNH541, 543, 545 21 —(CH2)2— Me2N 479, 481, 483 22 —(CH2)2— PhNH 527, 529,531 23 —(CH2)2— PhMeN 541, 543, 545 24 —(CH2)2— (4-HOPh) NH 543, 545,547 25 —(CH2)2— PhNHNH 542, 544, 546 26 —(CH2)3— iBuNH 521, 523, 525 27—(CH2)3— tBuNH 521, 523, 525 28 —(CH2)3— BnNH 555, 557, 559 29 —(CH2)3—Me2N 493, 495, 497 30 —(CH2)3— PhNH 541, 543, 545 31 —(CH2)3— (4-HOPh)NH 557, 559, 561

EXAMPLE 85 Synthesis ofN-[1-N,N-dimethylaminocarbonylcyclopropane-1-ylcarbonyl]-4-({[5-chloro-2-(methylthio)pyrimidine-4-yl]carbonyl}-amino)-L-phenylalanine:

[0171] Step 1 Introduction of Amino Acid into Resin:

[0172] 2.0 g of Wang resin (0.76 mmol/g) was alternately washed with NMPand DCM twice and then with NMP 3 times. A solution (11 ml) of 2.0 g ofFmoc-Phe(4-nitro)-OH in NMP, a solution (5 ml) of 0.87 ml of pyridine inNMP and a solution (4 ml) of 0.66 ml of 2,6-dichlorobenzoyl chloride inNMP were successively added to the resin, and the obtained mixture wasshaken at room temperature for 16 hours. The reaction solution wasremoved, and the resin was washed with DMF 3 times, with ethanol 3times, with DCM 3 times and with NMP 3 times. 7 ml of NMP, 7 ml of asolution of 1.49 ml of pyridine in NMP and 7 ml of a solution of 1.46 mlof acetic anhydride in NMP were added to the obtained resin. Aftershaking at room temperature for 2 hours, the reaction solution wasremoved, and the residue was washed with DMF 3 times, with ethanol 3times and with DCM 3 times. The obtained resin was dried under reducedpressure.

[0173] Step 2 Fmoc-Removing Reaction:

[0174] 42 ml of 20% solution of piperidine in DMF was added to the resinobtained as described above, and they were shaken for 5 minutes. Thereaction solution was removed, 42 ml of 20% solution of piperidine inDMF was added again to the residue, and they were shaken for 15 minutes.The reaction solution was removed, and the resin was washed with DMF 3times, with ethanol 3 times, with DCM 3 times, and again with DMF 3times.

[0175] Step 3 Acylation/Amidation Reaction:

[0176] A solution (12 ml) of 1.96 g of cyclopropanedicarboxylic acid inDMF, a solution (17 ml) of 2.05 g of HOAt in DMF and 2.29 ml of DIC weresuccessively added to the resin obtained in step 2. After shaking atroom temperature for 3.5 hours, the reaction solution was removed, andthe resin was washed with DMF 3 times, DCM 3 times and again with DMF 3times. A solution obtained by diluting 2M-THF solution (7.57 ml) ofdimethylamine with 12 ml of DMF was added to the resin. A solution (17ml) of 2.05 g of HOAt and 2.29 ml of DIC was added to the obtainedmixture, and they were shaken at room temperature for 15 hours. Thereaction solution was removed, and the residue was washed with DMF 3times, with ethanol 3 times and with DCM 3 times. The obtained resin wasdried under reduced pressure.

[0177] Step 4 Reduction of Nitro Group:

[0178] The resin obtained in step 3 was added to 50 ml of 2 M solutionof stannic chloride dihydrate in DMF to conduct the reaction at roomtemperature for 3 hours. The reaction solution was removed, and theresidue was washed with DMF, ethanol and DCM 3 times each. The obtainedresin was dried under reduced pressure.

[0179] Step 5 Acylation Reaction:

[0180] A solution (200 μl) of 13.5 mg of5-chloro-2-(methylthio)-pyrimidine-4-carboxylic acid in DMF, a solution(157 μl) of 34.3 mg of PyBOP in DMF, a solution (157 μl) of 14.9 mg ofHOBt in DMF and a solution (157 μl) of 23.0 μl of DIEA in DMF weresuccessively added to 40.0 mg of the resin obtained in step 4, and theywere shaken at room temperature for 23 hours. The reaction solution wasremoved, and the residue was washed with DMF, ethanol and DCM 3 timeseach.

[0181] Step 6 Removal of Resin:

[0182] 95% aqueous trifluoroacetic acid solution (1 ml) was added to theresin obtained in step 5, and they were shaken for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (1 ml) was added tothe resin, and they were shaken for 1 hour and then filtered. Thefiltrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 μm; 19mmφ×50 mm) of Waters Co., developer: water/acetonitrile (TFA 0.05%)],4.8 mg of the intended compound was obtained.

[0183] MS (ESI positive): 506

[0184] C₂₂H₂₄ClN₅O₅S: 505

EXAMPLES 86 TO 89 AND 106 TO 107

[0185] Compounds in the respective Examples were synthesized in the samemanner as that of Example 85 except that a corresponding carboxylic acidwas used in place of 5-chloro-2-(methylthio)pyrimidine-4-carboxylic acidused in step 5 in Example 85. D, E, K and L in Table 2-1 weresubstituents in general formula (1-2) given below. See Table 2-1.

EXAMPLE 90 Synthesis ofN-[1-(N,N-dimethylaminocarbonyl)-cyclopropane-1-ylcarbonyl]-4-{[2,6-dichlorophenylcarbonyl]amino}-L-phenylalanine

[0186] Step 1 Acylation Reaction:

[0187] A solution (250 μl) of 12.2 μl of pyridine in DCM and a solution(200 μl) of 13.5 μl of 2,6-dichlorobenzoyl chloride in DCM were added to51.2 mg of the resin obtained in step 4 in Example 85. After shaking atroom temperature for 15 hours, the reaction solution was removed and theresidue was washed with DMF, ethanol and DCM 3 times each.

[0188] Step 2 Removal of Resin:

[0189] 95% aqueous trifluoroacetic acid solution (800 μl) was added tothe resin obtained in step 1, and they were stirred for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (600 μl) was furtheradded to the resin and they were stirred for 1 hour and then filtered.The filtrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 μm; 19mmφ×50 mm) of Waters Co., developer: water/acetonitrile (TFA 0.05%)],5.4 mg of the intended compound was obtained.

[0190] MS (ESI positive): 494, 494, 496

[0191] C₂₃H₂₃Cl₁₂N₃O₅: 491, 493, 495

EXAMPLE 91 Synthesis ofN-[2-(pyrrolidine-1-ylcarbonyl)-2-ethyl-butanoyl]-4-{[(2,6-dichlorophenyl)carbonyl]amino}-L-phenylalanine:

[0192] Step 1 Acylation/Amidation Reaction:

[0193] A solution (250 μl) of 11.7 μl of pyridine in DCM and a solution(200 μl) of 12.9 μl of 2,6-dichlorobenzoyl chloride in DCM were added tothe resin (dry weight: 49.8 mg) obtained in the same manner as that instep 2 in Example 94. After shaking at room temperature for 15 hours,the reaction solution was removed and the residue was washed with DMF,ethanol and DCM 3 times each.

[0194] Step 2 Removal of Resin:

[0195] 95% aqueous trifluoroacetic acid solution (800 μl) was added tothe resin obtained in step 1, and they were shaken for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (600 μl) was furtheradded to the resin and they were stirred for 1 hour and then filtered.The filtrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 μm; 19mm φ×50 mm) of Waters Co., developer: water/acetonitrile (TFA0.05%)],2.5 mg of the intended compound was obtained.

[0196] MS (ESI positive): 548, 550, 552

[0197] C₂₇H₃₁Cl₂N₃O₅: 547, 549, 551

EXAMPLE 92 Synthesis ofN-(2-pyrrolidine-1-ylcarbonyl-2-ethyl-butanoyl)-4-({[2-fluoro-6-(trifluoromethyl)phenyl]carbonyl}amino)-L-phenylalanine

[0198] The same procedure as that of Example 91 was repeated except that2,6-dichlorobenzoyl chloride was replaced with2-fluoro-6-(trifluoromethyl)benzoyl chloride in step 1. D, E, K and L inTable 2-1 were substituents in general formula (1-2) given below. SeeTable 2-1.

[0199] MS (ESI positive): 566

[0200] C₂₈H₃₁F₄N₃O₅: 565

EXAMPLES 93, 95-99, 110-111 AND 477

[0201] Compounds in the respective Examples were synthesized in the samemanner as that of Example 94 except that5-chloro-2-(methylthio)pyrimidine-4-carboxylic acid used in step 3 inExample 94 was replaced with a corresponding carboxylic acid. D, E, Kand L in Table 2-1 were substituents in general formula (1-2) givenbelow. See Table 2-1.

EXAMPLE 94 Synthesis ofN-[2-(pyrrolidine-1-ylcarbonyl)-2-ethyl-butanoyl]-4-({[5-chloro-2-(methylthio)pyrimidine-4-yl]carbonyl}amino)-L-phenylalanine

[0202] Step 1 Acylation/Amidation Reaction:

[0203] 15 ml of 20% solution of piperidine in DMF was added to the resin(dry weight: 1.52 g) obtained in the same manner as that of step 1 inExample 85, and they were shaken for 5 minutes. The reaction solutionwas removed. 15 ml of 20% solution of piperidine in DMF was added againto the residue, and they were stirred for 15 minutes. The reactionsolution was removed, and the resin was washed with DMF, ethanol, DCMand NMP 3 times each. Separately, a solution (6 ml) of 680 mg ofdiethylmalonic acid and 1.74 g of HOAt in NMP was cooled with ice, and asolution (1 ml) of 1.98 ml of DIC in NMP was added thereto under coolingwith ice. After stirring under cooling with ice for 30 minutes and thenat room temperature for 30 minutes, the insoluble matter was removed bythe filtration. The filtrate was added to the resin obtained asdescribed above, and they were stirred at room temperature for 16 hours.The reaction solution was removed, and the resin was washed with DMF,DCM and NMP 3 times each. A solution (3 ml) of 493 μl of pyrrolidine inNMP, and then a solution (3 ml) of 810 mg of HOAt and 910 μl of DIC inNMP were added to the resin, and the reaction was conducted at roomtemperature for 16 hours. The reaction solution was removed, and theresin was washed with DMF, ethanol and DCM 3 times each.

[0204] Step 2 Reduction of Nitro Group:

[0205] The resin obtained in step 1 was added to 21 ml of 1.73 Msolution of stannic chloride dihydrate in NMP/EtOH (20:1) to conduct thereaction at room temperature for 3 hours. The reaction solution wasremoved, and the residue was washed with DMF, ethanol and DCM 3 timeseach. The obtained resin was dried under reduced pressure.

[0206] Step 3 Acylation Reaction:

[0207] A solution (180 μl) of 18.1 mg of5-chloro-2-(methylthio)-pyrimidine-4-carboxylic acid in DMF, a solution(141 μl) of 46.0 mg of PyBOP in DMF, a solution (141 μl) of 19.9 mg ofHOBt in DMF and a solution (141 μl) of 30.8 μl of DIEA in DMF weresuccessively added to 50.8 mg of the resin obtained in step 2, and theywere shaken at room temperature for 15 hours. The reaction solution wasremoved, and the residue was washed with DMF, ethanol and DCM 3 timeseach.

[0208] Step 4 Removal of Resin:

[0209] 95% aqueous trifluoroacetic acid solution (800 μl) was added tothe resin obtained in step 3, and they were shaken for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (600 μl) was addedto the resin, and they were shaken for 1 hour and then filtered. Thefiltrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 μm; 19mm φ×50 mm) of Waters Co., developer: water/acetonitrile (TFA 0.05%)],6.6 mg of the intended compound was obtained.

[0210] MS (ESI positive): 562

[0211] C₂₆H₃₂ClN₅O₅S: 561

EXAMPLES 108-109

[0212] Compounds in the respective Examples were synthesized in the samemanner as that of Example 90 except that a corresponding carboxylic acidchloride was used in place of 2,6-dichlorobenzoyl chloride used in step1 in Example 90. D, E, K and L in Table 2-1 were substituents in generalformula (1-2) given below. See Table 2-1.

EXAMPLE 478

[0213] Synthesis ofN-[2-(pyrrolidine-1-ylcarbonyl)-2-ethyl-butanoyl]-4-({[5-chloro-2-(methylsulfinyl)pyrimidine-4-yl]carbonyl}amino)-L-phenyl-alanine:

[0214] Step 1

[0215] A solution of 1.2 equivalents of 3-chloroperbenzoic acid in DCMwas added to the resin obtained in step 3 in Example 94 and then theywere shaken at room temperature for 1.5 hours. Then the reactionsolution was removed and the residue was washed with DMF, ethanol andDCM 3 times each.

[0216] Step 2

[0217] 95% aqueous trifluoroacetic acid solution (1 ml) was added to theresin obtained in step 1, and they were stirred for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (1 ml) was furtheradded to the resin and they were stirred for 1 hour and then filtered.The filtrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 μm; 19mm φ×50 mm) of Waters Co., developer: water/acetonitrile (TFA 0.05%)],the intended compound was obtained.

[0218] MS (ESI positive): 578 [MH]⁺

[0219] (ESI negative): 576 [M−H]⁻, 690 [M+TFA−H]⁻

[0220] C₂₆H₃₂ClN₅O₆S: 577

EXAMPLE 479 Synthesis ofN-[2-(pyrrolidine-1-ylcarbonyl)-2-ethyl-butanoyl)-4-({[5-chloro-2-(methylsulfonyl)pyrimidine-4-yl]carbonyl}-amino)-L-phenyl-alanine

[0221] Step 1

[0222] The resin obtained in step 3 in Example 94 was reacted with asolution of 5 equivalents of 3-chloroperbenzoic acid in DCM. Then thereaction solution was removed and the residue was washed with DMF,ethanol and DCM 3 times each.

[0223] Step 2

[0224] 95% aqueous trifluoroacetic acid solution (1 ml) was added to theresin obtained in step 1, and they were stirred for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (1 ml) was furtheradded to the resin and they were stirred for 1 hour and then filtered.The filtrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 i m; 19mm φ×50 mm) of Waters Co., developer: water/acetonitrile (TFA 0.05%)],the intended compound was obtained.

[0225] MS (ESI positive): 594 [MH]⁺

[0226] (ESI negative): 592 [M−H]⁻, 706 [M+TFA−H]⁻

[0227] C₂₆H₃₂ClN₅O₇S: 593

EXAMPLE 480 Synthesis ofN-[2-(pyrrolidine-1-ylcarbonyl)-2-ethyl-butanoyl]-4-[({5-chloro-2-[(4-methoxybenzyl)amino]pyrimidine-4-yl}carbonyl)amino]-L-phenylalanine

[0228] Step 1:

[0229] A solution of p-methoxybenzylamine (3 equivalents) in DMSO wasadded to the resin obtained in step 1 in Example 479. After shaking themat room temperature for 20 hours, the reaction solution was removed andthe residue was washed with DMF, ethanol and DCM 3 times each.

[0230] Step 2:

[0231] 95% aqueous trifluoroacetic acid solution (1 ml) was added to theresin obtained in step 1, and they were shaken for 1 hour and thenfiltered. 95% aqueous trifluoroacetic acid solution (1 ml) was furtheradded to the resin and they were stirred for 1 hour and then filtered.The filtrates were combined together and then concentrated. After thepurification by the reversed-phase HPLC [Symmetry C18 column (5 μm; 19mm φ×50 mm) of Waters Co., developer: water/acetonitrile (TFA 0.05%)],the intended compound was obtained.

[0232] MS (ESI positive): 651 [MH]⁺

[0233] (ESI negative): 649 [M−H]⁻, 763 [M+TFA−H]⁻

[0234] C₃₃H₁₉ClN₆O₆: 650

EXAMPLES 481-484

[0235] Compounds in the respective Examples were synthesized in the samemanner as that of Example 480 except that p-methoxybenzylamine used instep 1 in Example 480 was replaced with a corresponding amine. D, E, Kand L in Table 2-1 were substituents in general formula (1-2) givenbelow. See Table 2-1. TABLE 2-1 (1-2)

Example D E K L MS Found (MH+) 85 —(CH2)2— Me2N partial structure 5 50686 —(CH2)2— Me2N 2-Chloro-4,5-difluorophenyl 494 87 —(CH2)2— Me2N5-Bromo-2-Chlorophenyl 536 88 —(CH2)2— Me2N 2,5-Dibromophenyl 581 89—(CH2)2— Me2N 2-Bromo-5-methoxyphenyl 532 90 —(CH2)2— Me2N2,6-Dichlorophenyl 492, 494, 496 91 Et Et Pyrrolidino 2,6-Dichlorophenyl548, 550, 552 92 Et Et Pyrrolidino 2-Trifluoromethyl-5-fluorophenyl 56593 Et Et Pyrrolidino partial structure 6 564 94 Et Et Pyrrolidinopartial structure 5 562 95 Et Et Pyrrolidino 2-Chloro-4,5-difluorophenyl550 96 Et Et Pyrrolidino 5-Bromo-2-Chlorophenyl 593 97 Et Et Pyrrolidino2-Nitrophenyl 525 98 Et Et Pyrrolidino 2,5-Dibromophenyl 638 99 Et EtPyrrolidino 2-Bromo-5-methoxyphenyl 588 106 —(CH₂)₂— Me₂N partialstructure 6 508 107 —(CH₂)₂— Me₂N 2-Nitrophenyl 469 108 —(CH₂)₂— Me₂N2-Fluoro-6-(trifluoromethyl)phenyl 510 109 —(CH₂)₂— Me₂N2,6-Difluorophenyl 460 110 Et Et Pyrrolidino partial structure 7 539 111Et Et Pyrrolidino partial structure 8 581 477 Et Et Pyrrolidino partialstructure 8-1 606, 608 478 Et Et Pyrrolidino partial structure 8-2 578479 Et Et Pyrrolidino partial structure 8-3 594 480 Et Et Pyrrolidinopartial structure 8-4 651 481 Et Et Pyrrolidino partial structure 8-5585 482 Et Et Pyrrolidino partial structure 8-6 599 483 Et EtPyrrolidino partial structure 8-7 573 484 Et Et Pyrrolidino partialstructure8-8 545

Partial Structures

[0236]

EXAMPLES 112-260

[0237] Compounds in the respective Examples were synthesized in the samemanner as that of Example 85 except that5-chloro-2-(methylthio)pyrimidine-4-carboxylic acid was replaced with acorresponding carboxylic acid in step 5 and the purification by HPLC wasomitted. However, for a compound of the above formula wherein L has theunsubstituted amino group, the reaction is conducted by using acorresponding aminocarboxylic acid having an amino acid protected withBoc group. L in Table 2-1-1 is a substituent in the following generalformula 1-2-1: (1-2-1)

MS Found Example L—C(═O) (MH+) 112 2-Methyl-2-butenoyl 402 1131-Cyclohexene carbonyl 428 114 α-Ethyl-m-nitrocinnamoyl 523 1151-Phenyl-1-cyclopropanecarbonyl 464 116 1-Methylcyclopropane-1-carbonyl402 117 2,2-Dichloro-1-methylcyclopropanecarbonyl 470 1182,2-Dimethyl-3-(2,2-dimethylvinyl)cyclo- 470 propanecarbonyl 1199-Fluorenone-1-carbonyl 526 120 5-Methyl-2-(trifluoromethyl)-3-furoyl496 121 1-Phenyl-5-(tritluoramethyl)pyrazole-4-carbonyl 558 1221-Methyl-5-nitropirazole-4-carbonyl 473 1234-Bromo-1-ethyl-3-methylpyrazole-5-carbonyl 536 1243-(2-Chlorophenyl)-5-methylisoxazole-4-carbonyl 539 1252,4-Dimethylthiazole-5-carbonyl 459 1262-(1,4-Benzodioxan-2-yl)thiazole-4-carbonyl 565 1274,5-Dichloro-isothiazole-3-carbonyl 499 128 5-Bromo-2-furoyl 492 1292-Furoyl 414 130 5-Nitro-2-furoyl 459 131 3-Methyl-2-thenoyl 444 1323-Chloro-4-isoproylsulphonyl-5- 616 methylthio-2-thenoyl 1334-Methoxy-3-thenoyl 460 134 5-Methoxyindole-2-carbonyl 493 135Benzothiazole-6-carbonyl 481 136 8-Quinolinecarbonyl 475 1375,6-Dichloronicotinoyl 493 138 5-Bromonicotinoyl 503 1396-Chloropyridine-2-carbonyl 459 140 2H-Pyran-2-one-5-carbonyl 442 1412-(Methylthio)benzoyl 470 142 2-Phenylbenzoyl 500 143 2-Ethoxybenzoyl468 144 3-(Chloromethyl)benzoyl 472 145 4-Diethylaminobenzoyl 495 1464-Bromo-2-methylbenzoyl 516 147 4-Cyclohexylbenzoyl 506 1484-Phenoxybenzoyl 516 149 2,3,6-Trimethoxybenzoyl 514 1502,6-Dimethoxy-3-nitrobenzoyl 529 151 2,5-Difluorobenzoyl 460 1523-Aminosulfonyl-4-chlorobenzoyl 537 153 3,4-Dichlorobenzoyl 492 1544-Methyl-3-nitrobenzoyl 483 155 4-Dimethylamino-3,5-dinitrobenzoyl 557156 DL-2-[4-(Trifluoromethoxy)phenoxy]propanoyl 552 157 Crotonoyl 388158 trans-2-Ethoxycarbonyl-acryloyl 446 159 2-Thiopheneacryloyl 456 1603,4-Dichiorocinnamoyl 518 161 4-Methylcinnamoyl 464 162o-Chlorocinnamoyl 484 163 3-Fluorocinnamoyl 468 1641-(4-Chlorobenzyl)pyrrolidin-2-one-4-carbonyl 555 165 L-Pyroglutamyl 431166 Thioprolyl 435 167 Tryptophyl 506 168 Phenylglycyl 453 169Lys-(Cl-Z)- 616 170 Arg(Tos)- 630 171 Tyr(2-Br-Z)- 695 172 Asp(OcHex)-517 173 His(DNP)- 623 174 (2-Naphthoxy)acetyl 504 175p-(Trifluoromethyl)phenylacetyl 506 176 2-Iodophenylacetyl 564 1773,4-Dichlorophenylacetyl 506 178 (4-Fluorophenylthio)acetyl 488 179(3-Acetyl-2-methyl-5-oxo-2-pyrrolin-4-yl)acetyl 499 180 Vinylacetyl 388181 3-[1,2-Dihydro-2-oxo-3-(trifluoromethyl)- 537 pyrid-1-yl]propionyl182 3-(2-Benzoxazolin-2-on-3-yl)propionyl 509 183(5-Methyl-2-phenyloxazol-4-yl)acetyl 519 1843-(2-Metbyl-4-nitroimidazol-1-yl)propionyl 501 1853-(Methoxycarbonyl)propionyl 434 186 (3,4-Methylenedioxy)phenylacetyl482 187 R-(+)-α-Methoxy-α-(trifluoromethyl)phenylacetyl 536 1885-Chlorobicyclo[2.2.1]hept-2-en-5-endo-carbonyl 474 1895-Hydroxy-2-indolecarbonyl 479 190 Indole-2-carbonyl 463 1915-Methoxyindole-2-carbonyl 493 192 2-Thenoyl 430 193 3-Bromo-2-thenoyl508 194 5-Carboxy-2-thenoyl 474 195 5-Methyl-2-thenoyl 444 1964-Methoxy-3-thenoyl 460 197 Picolinoyl 425 198 5-Carboxypicolinoyl 469199 6-Carboxypicolinoyl 469 200 Nicotinoyl 425 201 2-Chloronicotinoyl459 202 2,6-Dimethoxynicotinayl 485 203 6-Chloronicotinoyl 459 2046-Methylnicotinoyl 439 205 2-Chloroisonicotinoyl 459 2063-Carboxypyrazine-2-carbonyl 470 207 Benzoyl 424 208N-Phenylanthraniloyl 515 209 2-Bromobenzoyl 502 210 2-Fluorobenzoyl 442211 2-Hydroxybenzoyl 440 212 2-Iodobenzoyl 550 213 o-Anisoyl 454 214o-Toluoyl 438 215 2-Phenoxybenzoyl 516 216 2-Benzoylbenzoyl 528 2173-Nitrobenzoyl 469 218 m-Bromobenzoyl 502 219 3-Fluorobenzoyl 442 220m-Hydroxybenzoyl 440 221 m-Iedobenzoyl 550 222 3-Nitrobenzoyl 469 223m-Anisoyl 454 224 3-Formylbenzoyl 452 225 3-Cyanobenzoyl 449 2203-Carboxybenzoyl 468 227 m-Toluoyl 438 228 3-Dimethylaminobeuzoyl 467229 3-Methoxycarbonylbenzoyl 482 230 3-Phenoxybenzoyl 516 2314-Dimethylaminobenzoyl 467 232 4-Isopropylbenzoyl 466 2334-Phenylbenzoyl 500 234 4-(Chloromethyl)benzoyl 472 2354-(Dihydroxyboryl)benzoyl 468 236 4-Iodobenzoyl 550 237 p-Anisoyl 454238 4-Formylbenzoyl 452 239 (p-Trifluoromethoxy)benzoyl 508 240(p-Trifluoromethyl)benzoyl 492 241 4-Acetamidobenzoyl 481 2424-Acetylbenzoyl 466 243 p-Ethylbenzoyl 452 2444-(Methoxyearbonyl)benzoyl 482 245 4-Vinylbenzoyl 450 2464-Isopropylbenzoyl 466 247 2-Methyl-3-nitrobenzoyl 483 2482,6-Dimethoxy-3-nitrobenzoyl 529 249 2,4-Dimethylbenzoyl 452 2502-Methoxy-4-xnethylthiobenzoyl 500 251 5-Bromosalicyloyl 518 2525-Chlorosalicyloyl 474 253 5-Formylsalicyloyl 468 2545-Methoxy-2-nitrobenzoyl 499 255 3-Bromo-4-methylbenzoyl 516 2563-Iodo-4-methylbenzoyl 564 257 4-Methoxy-3-nitrobenzoyl 499 2583-Methoxy-4-nitrobenzoyl 499 259 4-Methyl-3-nitrobenzoyl 483 2603,4-Dimethoxybenzoyl 484

EXAMPLES 100 TO 103, 261, 263-273 AND 476

[0238] The compounds shown below were synthesized by using acorresponding dicarboxylic acid, amine and alkyl bromide in the samemanner as that of steps 1 to 2 in Example 94 and Example 262. D, E and Lin Table 2-2 are substituents in general formula (1-3) shown below. InExamples 261 and 273, the alkylation in step 2 in Example 262 wasomitted and the resin was removed in step 3.

EXAMPLE 262 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-[1-allyl-2,4-dioxo-1,4-dihydroquinazoline-3(2H)-yl]-L-phenylalanine

[0239] Step 1 Construction of Quinazolidine-1,4-dione Ring by UreaSynthesis and Ring Closure:

[0240] 2 g of a resin obtained from 1,1-cyclopropanedicarboxylic acidand pyrrolidine in the same manner as that of steps 1 and 2 in Example94 was added to a solution of methyl-2-isocyanate benzoate (1.92 g) inNMP (32 ml) to conduct the reaction for 16 hours. The reaction solutionwas removed, and the resin was washed with DMF and DCM 3 times each.Then 20% solution of piperidine in DMF was added to the resin to conductthe reaction for 1 hour. The reaction solution was removed, and theresin was washed with DMF and DCM 3 times each and then dried underreduced pressure.

[0241] Step 2 Alkylation:

[0242] Allyl bromide (0.75 mmol), 18-crown-6 (30 mg), NMP (1 ml) andK₂CO₃ (35 mg) were added to 20 mg of the resin obtained in step 1 toconduct the reaction for 3 days. The reaction solution was removed, andthe resin was washed with DMF, water, DMF and dichloromethane 3 timeseach and then dried under reduced pressure.

[0243] Step 3 Removal of Resin:

[0244] The resin obtained in step 3 was treated with 95% aqueoustrifluoroacetic acid solution for 1 hour. The resin was filtered out.The residue was concentrated under reduced pressure. Then 0.2 ml ofwater and 0.2 ml of acetonitrile were added to the concentrate and theobtained mixture was freeze-dried.

[0245] MS (ESI positive): 531

[0246] C₂₉H₃₀N₄O₆: 530 TABLE 2-2 (1-3)

MS Found Example D E L (MH+) 261 Et Et hydrogen 521 262 —(CH₂)₂— Allyl530 263 —(CH₂)₂— 2,6-difluorobenzyl 617 264 —(CH₂)₂—4-pirrolidinephenacyl 678 265 —(CH₂)₂— 2,6-dichlorobenzyl 649 266—(CH₂)₂— 4-nitrobenzyl 625 267 —(CH₂)₂— phenylthioethyl 627 268 —(CH₂)₂—2,4-bis(trifluoromethyl)benzyl 717 269 —(CH₂)₂— cyanomethyl 530 270—(CH₂)₂— cinnamyl 607 271 —(CH₂)₂— 2-naphtylmethyl 631 272 —(CH₂)₂—methoxycarbonylmethyl 563 273 —(CH₂)₂— hydrogen 491 100 Et Et2-naplitylmethyl 661 101 Et Et cinnamyl 637 102 Et Et 2-propynyl 559 103Et Et methoxycarbonylmethyl 593 476 Et Et Methyl 535

EXAMPLE 274 Synthesis ofN-(2-pyrrolidine-1-ylcarbonyl-2-ethyl-butanoyl)-4-[4-oxoquinazoline-3(4H)-yl]-L-phenylalanine

[0247] Step 1: Preparation of Resin:

[0248] 1 g of the resin obtained in steps 1 and 2 in Example 94 wasadded to a mixture of 2-nitrobenzoyl chloride (3.15 ml), 2,6-lutidine(2.8 ml) and NMP (24 ml) for 16 hours. The reaction solution was removedand the resin was washed with DCM and DMF 3 times each. The resin wasadded to a mixture of SnCl₂·H₂O (10 g), NMP (21 ml) and ethanol (1.1 ml)to conduct the reaction for 16 hours. The reaction solution was removed,and the resin was washed with DMF and DCM 3 times each.

[0249] Step 2 Removal of Resin:

[0250] 20 mg of the resin obtained in step 1 was treated with a mixtureof trimethyl o-formate (0.6 ml), acetic acid (50 μl) and NMP (0.6 ml) at50° C. for 16 hours. The resin was filtered out, and the residue wasconcentrated under reduced pressure. Then 0.2 ml of water and 0.2 ml ofacetonitrile were added to the concentrate and the obtained mixture wasfreeze-dried.

[0251] MS (ESI positive): 505

[0252] [C₂₈H₃₂N₄O₅: 504]

EXAMPLES 275-278

[0253] Compounds listed below were synthesized in the same manner asthat of Example 274 except that a corresponding orthoformate was used. Lin Table 2-2-1 was a substituent in general formula (1-3-1) given below.TABLE 2-2-1 (1-3-1)

Example L MS Found (MH+) 274 H 505 275 Me 519 276 MeO 535 277 propyl 547278 Phe 581

EXAMPLE 279 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)-cyclopropane-1-ylcarbonyl]-4-{(7aS)-1,3-dioxo-tetrahydro-1H-pyrolo[1,2-C]imidazole-2(3H)-yl}-L-phenylalanine

[0254] Step 1 Preparation of Resin:

[0255] 20 mg of the resin obtained in steps 1 to 4 in Example 85 wasadded to a mixture of 0.3 mmol of Fmoc-Pro-OH, 156 mg of PyBOP, 68 mg ofHOBt and 105 μl of DIEA to conduct the reaction for 16 hours. The resinwas washed with DMF and DCM 3 times each. After the reaction with 20%solution of piperidine in DMF for 1 hour, the reaction solution wasremoved and the resin was washed with DMF and DCM 3 times each. Afterreacting the resin with 49 mg of carbonyldiimidazole in the form of asolution (3 ml) in DCM for 30 minutes, the reaction solution was removedand the residue was washed with anhydrous DCM 5 times and then thereaction was carried out in DCM (2 ml) for 3 hours. The reactionsolution was removed and the resin was washed with DCM 3 times and thendried under reduced pressure.

[0256] Step 2 Removal of the Resin:

[0257] 20 mg of the resin obtained in step 1 was treated with 95%aqueous trifluoroacetic acid solution for 1 hour. The resin was taken bythe filtration. After the concentration under reduced pressure, water(0.2 ml) and acetonitrile (0.2 ml) were added to the residue and theproduct was freeze-dried.

[0258] MS (ESI positive): 443

[0259] [C₂₂H₂₆N₄O₆: 442]

EXAMPLES 280 TO 282 AND 458

[0260] The compounds listed below were synthesized in the same manner asthat of Example 279 except that a corresponding amino acid was used. Land M in Table 2-2-2 each was a substituent in general formula (1-3-2)given below. TABLE 2-2-2 (1-3-2)

Example L M MS Found (MH+) 279 —CH2—CH2—CH2— 443 280 H Cyclohexylmethyl499 281 H Benzyl 493 282 H Methyl 417 458 H Isopropyl 445

EXAMPLE 283 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2-cyclopentyl-ethyl)-L-tyrosine

[0261] Step 1 Preparation of Resin:

[0262] 2.0 g of Wang resin (0.89 mmol/g) was washed with NMP once. Thena solution (20 ml) of 2.5 g of Fmoc-Tyr(2-chlorotrityl)-OH, 0.5 ml of2,6-dichlorobenzoyl chloride and 0.5 ml of pyridine in DMF was added tothe resin, and the mixture were shaken at room temperature for 16 hours.The superfluous solvent was removed, and the resin was washed with DMF 3times, with DCM 3 times and with DMF twice. The obtained resin wastreated with 20% solution of piperidine in DMF at room temperature for 1hour. The solvent was removed and the resin was treated with DMF and DCM3 times each and then dried under reduced pressure.

[0263] Step 2 Acylation Reaction:

[0264] 100 mg of the resin obtained in step 1 was added to a solution of200 mg of 1, 1-cyclopropanedicarboxylic acid, 210 mg of HOAt, 240 μl ofDIC and 2.0 ml of DMF to conduct the reaction at room temperature for 16hours. The reaction solution was removed and the residue was washed withanhydrous DCM 5 times. The reaction was carried out in 3.0 ml of 2 Msolution of dimethylamine in THF and a solution of 480 mg of HOAt and520 μl of DIC in 4 ml of DMF for 16 hours. The reaction solution wasremoved and the resin was washed with DMF and DCM 3 times each and thendried under reduced pressure.

[0265] Step 3 Removal of 2-chlorotrityl Group:

[0266] The whole amount of the resin obtained in step 2 was washed withDCM 3 times and then treated with a mixed solution of 5.7 ml of DCM, 60μl of TFA and 900 μl of TIPS for 2 minutes repeatedly 3 times. Then theresin was washed with DCM 5 times and dried under reduced pressure.

[0267] Step 4 Mitsunobu Reaction:

[0268] 20 mg of the resin obtained in step 3 was added to a mixture of103 mg of TMAD, 3157 mg of PPh, 1.6 ml of DCM and 69 μl of cyclopentaneethanol to conduct the reaction for 16 hours. The reaction solution wasremoved, and the resin was washed with DCM, DMF and DCM twice each andthen dried under reduced pressure.

[0269] Step 5 Removal of Resin:

[0270] The resin obtained in step 4 was treated with 95% aqueoustrifluoroacetic acid solution for 1 hour, then filtered and concentratedunder reduced pressure. 0.2 ml of water and 0.2 ml of acetonitrile wereadded thereto and the product was freeze-dried.

[0271] MS (ESI positive): 417

[0272] [C₂₃H₃₂N₂O₅: 416]

EXAMPLES 284-298

[0273] The compounds listed below were synthesized in the same manner asthat of Example 284 except that a corresponding alcohol was used. D inTable 2-2-3 was a substituent in general formula (1-3-3) given below.TABLE 2-2-3 (1-3-3)

Example D MS Found (MH+) 283 2-cyclopentylethyl 417 284 ethyl 349 285cyclopentyl 389 286 cyclohexylmethyl 417 287 cycloheptyl 417 288propinyl 359 289 3-phenoxybenzyl 503 290 pyridin-3-ylmethyl 412 291pyridin-2-ylmethyl 412 292 2-phenethyl 425 293 3-pyridin-3-ylpropyl 440294 2-thiophen-2-ylethyl 431 295 2-(benzyloxy)ethyl 456 2962-(2-naphtyl)ethyl 475 297 2-indanyl 437 298 cyclobutylmethyl 389

EXAMPLE 299 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-phenyl-L-phenyl-alanine

[0274] Step 1 Preparation of Resin:

[0275] 1.4 g of Wang resin (0.89 mmol/g) was washed with NMF once. Thena solution (25 ml) of 2.5 g of Fmoc-Phe(4-I)—OH, 0.66 ml of2,6-dichlorobenzoyl chloride and 1.3 ml of pyridine in DMF was added tothe resin, and the mixture was shaken at room temperature for 16 hours.The superfluous solvent was removed, and the resin was washed with DMF 3times, with DCM 3 times and DMF twice. The obtained resin was treatedwith 20% solution of piperidine in DMF at room temperature for 1 hour.The solvent was removed and the resin was washed with DMF and DCM 3times each and then dried under reduced pressure. The acylation reactionwas conducted in the same manner as that of step 2 in Example 283.

[0276] Step 2 Suzuki Reaction:

[0277] 20 mg of the resin obtained in step 1 was added to a solution ofphenylboric acid (0.015 mmol), PdCl₂ (dppf), CH₂Cl₂ (0.015 mmol), TEA(0.75 ml) and DMF (1.05 ml) to conduct the reaction at 80° C. for 24hours. The reaction solution was removed and the resin was washed withanhydrous DMF 8 times and with DCM 3 times, and then dried under reducedpressure.

[0278] Step 3 Removal of Resin:

[0279] The resin obtained in step 2 was treated with 95% aqueoustrifluoroacetic acid solution (1.5 ml) for 1 hour, then filtered and thefiltrate was concentrated under reduced pressure. After the purificationby the reversed-phase HPLC [Inertsil ODS, developer: water, acetonitrile(TFA 0.05%)], 0.7 mg of the intended compound was obtained.

[0280] MS (ESI positive): 381

[0281] C₂₂H₂₄N₂O₄: 380

EXAMPLES 300-306

[0282] The compounds listed below were synthesized in the same manner asthat of Example 299 except that a corresponding boric acid was used.

[0283] D in Table 2-2-4 was a substituent in general formula (1-3-4)given below. TABLE 2-2-4 (1-3-4)

Example D MS Found (MH+) 299 phenyl 381 300 2-benzofuranyl 421 3012-thiophenyl 387 302 3-pyridyl 382 303 2-benzothiophenyl 437 3042-methoxyphenyl 411 305 2-methylphenyl 395 306 2-chlorophenyl 415

EXAMPLE 105 Synthesis ofN-[3-(dimethylamino)-2,2-dimethyl-3-oxopropanoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine

[0284] Step 1 Synthesis of Hydrochloride of Methyl Ester of4-(2,6-dimethoxyphenyl)-L-phenylalanine Hydrochloride:

[0285] 15.1 g of Boc-Tyr-OMe was dissolved in 70 ml of methylenechloride. 20.6 ml of pyridine was added to the obtained solution. 9.41ml of anhydrous trifluoromethanesulfonic acid was added dropwise to theobtained mixture at 0° C. After stirring at 0° C. for 1 hour, thereaction mixture was diluted with 100 ml of methylene chloride and thenwashed with a saturated aqueous ammonium chloride solution (100 ml) andthen with water (100 ml×2). The organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure to obtain21.9 g (100%) of the intended compound.

[0286] 1 H-NMR (CDCl3) δ=1.43 (9H, s), 3.05 (1H, dd, J=6.6, 14.0 Hz),3.19 (1H, dd, J=5.7, 14.0 Hz), 3.73 (3H, s), 4.59-4.65 (1H, m), 5.03(1H, d, J=6.9 Hz), 7.20-7.27 (4H, m)

[0287] 9.80 g of the compound obtained as described above was dissolvedin 170 ml of DME under argon atmosphere. 12.6 g of potassium carbonate,5.01 g of 2,6-dimethoxyphenylboronic acid and 2.65 g oftetrakis(triphenylphosphine) palladium (0) were added to the obtainedsolution. The reaction mixture was stirred at 70° C. for 6 hours andthen dissolved in 150 ml of water. After the extraction with ethylacetate (150 ml×3), the organic layers were combined together and thendried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by the silica gel columnchromatography to obtain 8.64 g (91%) of the intended compound.

[0288] 1H-NMR (CDCl3) δ=1.55 (9H, s), 3.09-3.16 (2H, m), 3.72 (6H, s),3.74 (3H, s), 4.59-4.66 (1H, m), 5.01-5.06 (1H, m), 6.65 (2H, d, J=8.7Hz), 7.15-7.30 (5H, m)

[0289] 8.64 g of the compound thus obtained was dissolved in 4 Nhydrochloric acid/ethyl acetate solution (100 ml), and the obtainedsolution was stirred for 4 hours. The crystals thus precipitated weretaken by the filtration and then washed with ethyl acetate. The crystalswere dried to obtain 7.01 g (96%) of intended hydrochloride of methylester of 4-(2,6-dimethoxyphenyl)-L-phenylalanine hydrochloride in theform of white crystals.

[0290] 1H-NMR (CDCl3) δ=3.47 (2H, t, J=5.4 Hz), 3.71 (6H, s), 3.81 (3H,s), 4.43 (1H, t, J=5.4 Hz), 6.63 (2H, d, J=8.4 Hz), 7.24-7.35 (5H, m),8.73 (2H, br s)

[0291] MS (ESI positive): 316

[0292] [C₁₈H₂₁NO₄·HCl: 315 36.5]

[0293] Step 2 Acylation Reaction:

[0294] 35.2 mg of hydrochloride of methyl ester of4-(2,6-dimethoxyphenyl)-L-phenylalanine hydrochloride obtained in step 1was dissolved in DCM (1 ml) containing one drop of DIEA. The obtainedsolution was added dropwise to a suspension (1 ml) of 23.7 mg of3-(dimethylamino)-2,2-dimethyl-3-oxopropanoic acid and PS-carbodiimide(1.15 mol/g, 174 mg) in DCM. After stirring at room temperatureovernight, the reaction mixture was filtered The filter was thoroughlywashed with methylene chloride. The filtrate and the wash solution werecombined together and concentrated under reduced pressure. After thepurification by a silica gel column chromatography, 23.1 mg of theintended compound was obtained.

[0295] 1H-NMR (CDCl3) δ=1.23 (3H, s), 1.41 (3H, s), 2.51(3H, s), 2.81(3H, s), 2.85 (1H, dd, J=10.1, 14.3 Hz), 3.30 (1H, dd, J=4.4, 14.3 Hz),3.71 (6H, s), 3.76 (3H, s), 4.86-4.94 (1H, m), 5.77 (1H, d, J=8.4 Hz),6.64 (2H, d, J=8.0 Hz), 7.16 (2H, d, J=8.0 Hz), 7.22-7.30 (3H, m)

[0296] Step 3 Demethylation Reaction:

[0297] 23.1 mg of the compound obtained in step 2 was dissolved in 1 mlof a solvent mixture of methanol/THF. A solution of 25.6 mg of lithiumhydroxide in 0.5 ml of water was added to the obtained solution Theywere stirred at room temperature for 3 hours and then diluted with 1 Naqueous sodium hydroxide solution (10 ml). The reaction mixture waswashed with 10 ml of DCM twice, and the aqueous layer was adjusted to pH2 with 1 N hydrochloric acid. After the extraction with 10 ml of DCM 3times, the organic layers were combined together, dried over anhydroussodium sulfate and concentrated under reduced pressure. 18.6 mg (83%) ofthe intended compound was obtained in the form of a white powder.

[0298] 1H-NMR (CDCl3) δ=11.31 (3H, s), 1.41 (3H, s), 2.44(3H, s), 2.81(3H, s), 2.99 (1H, dd, J=110.5, 14.3 Hz), 3.40 (1H, dd, J=4.5, 14.3 Hz),3.70 (6H, s), 4.89-4.97 (1H, m), 6.41 (1H, br s), 6.64 (2H, d, J=8.4Hz), 7.22-7.30 (5H, m)

[0299] MS (ESI positive): 443

[0300] [C₂₄H₃₀N₂O₆·HCl: 442]

EXAMPLE 307 Synthesis of N-[2-ethyl-2-(pyrrolidine-1-ylcarbonyl)butanoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine

[0301] Step 1 Synthesis of HOAt Ester:

[0302] 640 mg of diethylmalonic acid and 1.63 g of HOAt were dissolvedin 10 ml of NMP. 1.86 ml of DICD was added to the obtained solution.After stirring at room temperature for 1.5 hours, 5 ml of a solution of704 mg of hydrochloride of methyl ester of4-(2,6-dimethoxyphenyl)-L-phenylalanine and 0.35 ml of DIEA in NMP wasadded dropwise to the reaction mixture. They were stirred for additional2 hours, and the reaction solution was diluted with 100 ml of ethylacetate. The reaction mixture was washed with saturated aqueous sodiumchloride solution (100 ml×2) and then with 100 ml of water. The organiclayer was dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The residue was purified by the silica gelcolumn chromatography to obtain 1.15 g (100%) of the intended compound.

[0303] 1H-NMR (CDCl3) δ=0.91 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.5 Hz),2.18-2.32 (4H, m), 3.07 (1H, dd, J=7.2, 13.1 Hz), 3.29 (1H, dd, J=5.4,13.1 Hz), 3.69 (6H, s), 3.75 (3H, s), 4.95-5.02 (1H, m), 6.64 (2H, d,J=8.4 Hz), 7.16-7.30 (5H, m), 7.46 (1H, dd, J=4.5, 8.4 Hz), 7.72 (1H, d,J=8.1 Hz), 8.44 (1H, dd, J=1.5, 8.4 Hz), 8.71 (1H, dd, J=1.5, 4.5 Hz)

[0304] Step 2 Synthesis of Methyl Ester ofN-[2-ethyl-2-(pyrrolidine-1-ylcarbonyl)butanoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine:

[0305] 57.5 mg of the compound obtained in step 1 was dissolved in 3 mlof NMP. 9.88 μl of pyrrolidine was added to the obtained solution. Themixture was stirred for 30 minutes and then diluted with 10 ml of 1 Naqueous hydrochloric acid solution. After the extraction with ethylacetate (10 ml×3), the organic layers were combined together and washedwith water (10 ml×3). The organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The residue waspurified by the silica gel column chromatography to obtain 38.2 mg (75%)of methyl ester ofN-[2-ethyl-2-(pyrrolidine-1-ylcarbonyl)butanoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine.

[0306] 1H-NMR (CDCl3) δ=0.61 (3H, t, J=7.5 Hz), 0.75 (3H, t, J=7.5 Hz),1.64-2.00 (8H, m), 2.91 (1H, dd, J=9.5, 14.0 Hz), 3.09-3.14 (1H, m),3.21 (1H, dd, J=4.8, 14.0 Hz), 3.29-3.35 (1H, m), 3.41-3.49 (2H, m),3.71 (6H, s), 3.74 (3H, s), 4.82-4.89 (1H, m), 6.05 (1H, d, J=7.5 Hz),6.64 (1H, d, J=8.7 Hz), 7.16 (2H, d, J=8.1 Hz), 7.24-7.29 (3H, m)

[0307] MS (ESI positive): 511

[0308] [C₂₉H₃₈N₂O₆: 510]

[0309] Step 3 Demethylation Reaction:

[0310] The same procedure as that of step 3 in Example 105 was repeatedto obtain the intended compound.

[0311] 1H-NMR (CDCl3) δ=0.59 (3H, t, J=7.5 Hz), 0.74 (3H, t, J=7.5 Hz),1.74-2.00 (8H, m), 2.99 (1H, dd, J=9.5, 14.2 Hz), 3.09-3.17 (1H, m),3.31 (1H, dd, J=4.8, 14.2 Hz), 3.28-3.48 (1H, m), 3.40-3.48 (2H, m),3.70 (6H, s), 4.82-4.89 (1H, m), 6.55 (1H, d, J=6.9 Hz), 6.63 (1H, d,J=8.7 Hz), 7.21-7.29 (5H, m)

[0312] MS (ESI positive): 497

[0313] [C₂₈H₃₆N₂O₆: 496]

EXAMPLES 104 AND 308 TO 342

[0314] The compounds listed below were synthesized in the same manner asthat of Example 307 except that a suitable reagent was used. D, E and Kin Table 2-3 were substituents in general formula (1-4) given below.TABLE 2-3 (1-4)

Example D E K MS Found(MH+) 104 Et Et dimethylamino 471 105 Me Medimethylamino 443 307 Et Et pyrrolidin-1-yl 497 308 Et Et3R-3-hydroxypyrrolidin-1-yl 513 309 Et Et3R-3-(dimethylamino)pyrrolidin-1-yl 540 310 Et Et3S-3-(acetylamino)pyrrolidin-1-yl 554 311 Et Et3R-3-(acetylamino)pyrrolidin-1-yl 554 312 Et Et(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl 524 313 Et methoxyethylR-3-hydroxypyrrolidin-1-yl 543 314 Et Et ethyl(methyl)amino 485 315 EtEt diethylamino 499 316 Et Et tert-butylamino 499 317 Et Etpiperidin-1-yl 511 318 Et Et morpholin-4-yl 513 319 Et Et azepan-1-yl525 320 Et Et benzyl(methyl)amino 547 321 Et Et (2-methoxyethyl)amino501 322 Et Et (2-hydroxyethyl)methylamino 501 323 Et Et(3-hydroxypropyl)amino 501 324 Et Et (4-hydroxybutyl)amino 515 325 Et Et(2-hydroxy-1,1-dimethylethyl)amino 515 326 Et Et 3-hydroxypiperidin-1-yl527 327 Et Et 4-hydroxypiperidin-1-yl 527 328 Et Et(4-hydroxycyclohexyl)amino 541 329 Et Et 3-(hydroxymethyl)piperidin-1-yl541 330 Et Et (2-methoxybenzyl)amino 563 331 Et Et(3-methoxybenzyl)amino 563 332 Et Et (4-methoxybenzyl)amino 563 333 EtEt (2-phenoxyethyl)amino 563 334 Et Et (2-furylmethyl)amino 523 335 EtEt (pyridin-2-ylmethyl)amino 534 336 Et Et (pyridin-3-ylmethyl)amino 534337 Et Et (pyridin-4-ylmethyl)amino 534 338 Et Et(pyrazin-2-ylmethyl)amino 535 339 Et Et[3-(1H-imidazol-1-yl)propyl]amino 551 340 Et Et[3-2-oxopyrrolidin-1-yl)propyl]amino 568 341 Et Et(2-hydroxycyclohexyl)amino 541 342 Et Et dimethylamino 471

EXAMPLE 343 Synthesis ofN-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-[(2-methylphenyl-sulfonyl)amino]-L-phenylalanine

[0315] 120 mg of the resin obtained in the same manner as in steps 1 to4 in Example 85 was added to a solution of 200 mg of2-methylbenzenesulfonyl chloride, 400 μl of 2,6-lutidine and 2 ml ofdichloromethane to conduct the reaction at 0° C. for 24 hours. Thereaction solution was removed, and the resin was washed withdichloromethane, NMP and dichloromethane 3 times each. The obtainedresin was treated with 100% trifluoroacetic acid for 1 hour and thenfiltered. The obtained solution was concentrated and then purified bythe reversed phase HPLC (SYMMETRY 19*50 mm mobile phase,water/acetonitrile each containing 0.1% of TFA) to obtain 2.0 mg of theintended compound.

[0316] MS (ESI positive): 474

[0317] [C₂₃H₂₇N₃O₆S: 473]

EXAMPLES 344 TO 362

[0318] The sulfonamides (general formulae 1-5 and 1-6) listed below weresynthesized in the same manner as that of Example 343 except that acorresponding sulfonyl chloride was used. L₁ in Table 2-4 and L₂, L₃,L₄, L₅ and L₆ in Table 2-5 are each a substituent in general formulae(1-5 and 1-6) given below. TABLE 2-4 (1-5)

Example L1-SO2— MS Found (MH+) 344 2-Bromobenzenesulfonyl 539 3452-(Methoxycarbonyl)benzenesulfonyl 518 3465-Bromo-2-methoxybenzenesulfonyl 569 3472,4,6-Triisopropylbenzenesulfonyl 586 348 Quinoline-8-sulfonyl 511 349Dansyl 553 350 2-Acetamido-4-methyl-5-thiazolesulfonyl 538 3515-Bromothiophene-2-sulfonyl 545 352 partial structure 9 534, 536 353partial structure 10 534 354 partial structure 11 466

[0319]

TABLE 2-5 (1-6)

Example L2 L3 L4 L5 L6 MS Found (MS+) 355 Me H Me H Me 502 356 CF3 H H HH 528 357 Cl H H H Cl 528, 530, 532 358 OMe H Me H H 504 359 OMe H OMe HH 520 360 H CF3 H H H 528 361 CN H H H H 485 362 Me H H NO2 H 519

EXAMPLES 363 TO 379

[0320] The carboxylic acids (general formula 1-7) listed below weresynthesized in the same manner as that of step 3 in Example 85 exceptthat an amine and pyrrolidine were used and in the same manner as thatof Example 343 except that a corresponding sulfonyl chloride was used.L7, L8, L9, L10 and L11 in Table 2-6 are each a substituent in generalformula (1-7) given below. TABLE 2-6 (1-7)

Example L7 L8 L9 L10 L11 MS Found (MH+) 363 OMe H H Br H 625 364 Br H HH H 595 365 Cl Cl Cl H H 618 366 Me Me OMe H Me 588 367 Me H Cl Me H 578368 Me Me H Me Me 572 369 Me Me Me Me Me 586 370 Cl H Cl Cl H 618 371 ClH Cl H Cl 618 372 Me Cl H H H 564 373 Cl H H Cl H 584 374 Cl H H H H 550375 Cl Cl H H H 584 376 Cl H Cl H H 584 377 Me H H F H 548 378 F H H H H534 379 Me H H NO2 H 575

EXAMPLE 380 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-(ethyl{[4-(trifluoro-methyl)phenyl]sulfonyl}amino)-L-phenylalanine

[0321] A corresponding sulfonamide resin was obtained in the same manneras that of Example 343 except that 4-trifluoromethylbenzenesulfonylchloride was used. 200 μl of ethyl bromide, 600 mg of potassiumcarbonate and 1 ml of NMP were added to 30 mg of the resin. The obtainedsolution was shaken at 35° C. for 24 hours. The reaction solution wasremoved, and the resin was washed with DCM, NMP and DCM 3 times each.The obtained resin was treated with trifluoroacetic acid for 1 hour andthen filtered out. The obtained solution was concentrated to obtain theintended compound without the purification.

[0322] MS (ESI positive): 556

[0323] [C₂₅H₂₈F₃N₃O₆S: 555]

EXAMPLES 381 TO 390

[0324] Carboxylic acids (general formula 1-8) were obtained by usingcorresponding sulfonyl chlorides in the same manner as that of Example343. 200 μl of a corresponding bromide, 600 mg of potassium carbonateand 1 ml of NMP were added to 30 mg of the sulfonamide resin thusobtained, and the obtained solution was shaken at 35° C. for 24 hours.The reaction solution was removed, and the resin was washed with DCM,NMP and DCM 3 times each. The obtained resin was treated withtrifluoroacetic acid for 1 hour and then filtered out. The obtainedsolution was concentrated to obtain the intended compound without thepurification.

[0325] L₁₂, L₁₃, L₁₄, L₁₅ and L₁₆ in Table 2-7 are each a substituent ingeneral formula (1-8) given below. TABLE 2-7 (1-8)

Ex- MS Found ample L12 L13 L14 L15 L16 L17 (MH+) 381 H H CF3 H H CN 567382 H H tBu H H CN 555 383 H H Cl H H CN 534 384 H H Me H H CN 513 385 HH Ph H H CN 575 386 H H CF3 H H 2-CN—Ph 643 387 H H CF3 H H CH2CH 568388 H H CF3 H H 2-Cl—Ph 653 389 H H CF3 H H 2-NO2—Ph 663 390 H H CF3 H H2,6-DiCl—Ph 687

EXAMPLES 391 TO 397

[0326] Carboxylic acids (general formula 1-9) were obtained by usingcorresponding sulfonyl chlorides in the same manner as that of Example343. 200 μl of a corresponding bromide, 600 mg of potassium carbonateand 1 ml of NMP were added to 30 mg of the sulfonamide resin thusobtained, and the obtained solution was shaken at 35° C. for 24 hours.The reaction solution was removed, and the resin was washed withdichloromethane, NMP and dichloromethane 3 times each. The obtainedresin was treated with trifluoroacetic acid for 1 hour and then filteredout. The obtained solution was concentrated to obtain the intendedcompound without the purification.

[0327] L₁₈ and L₁₉ in Table 2-8 are each a substituent in generalformula (1-9) given below. TABLE 2-8 (1-9)

Example L18 L19 MS Found (MH+) 391 Et CN 451 392 2-Naphthyl CN 549 3931-Naphthyl CN 549 394 Benzyl 2-CN—Ph 589 395 partial structure 12 CN 466396 partial structure 13 2-CN—Ph 645 397 partial structure 14 Et 721

[0328]

EXAMPLE 398 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-({4-[(4-diethyl-amino)carbonyl]-2-nitrophenyl}amino)-L-phenylalanine

[0329] The carboxylic acid was synthesized as follows: 200 mg of4-fluoro-5-nitrobenzoic acid was added to 30 mg of a resin having ananiline structure obtained by reducing nitro group in the same manner asthat of step 4 in Example 85. 500 μl of DMSO was added thereto and thereaction was conducted at 45° C. for 48 hours. The reaction solution wasremoved and the resin was washed with DCM, NMP and DCM 3 times each. Theobtained resin was reacted with diethylamine in the same manner as inthe synthesis of the amido bond in step 5 in Example 85. The obtainedresin was treated with trifluoroacetic acid for 1 hour and then filteredout. The filtrate was concentrated to obtain the intended compoundwithout the purification.

[0330] MS (ESI positive): 540

[0331] [C₂₇H₃₃F₃N₅O₇: 539]

EXAMPLES 399 TO 410

[0332] In those Examples, carboxylic acids (general formula 1-10) weresynthesized by using a corresponding benzoic acid and a correspondingamine or only a benzene derivative without the amine in the same manneras that of Example 398.

[0333] L₂₀, L₂₁, L₂₂, L₂₃ and L₂₄ in Table 2-9 are each a substituent ingeneral formula (1-10) given below. TABLE 2-9 (1-10)

Example L20 L21 L22 L23 L24 MS Found (MH+) 398 NO2 H Et2NCO H H 540 399NO2 H H H Et2NCO 540 400 NO2 H 2-Et2NCO-Benzoyl H H 589 401 Et2NCO H NO2H H 540 402 Et2NCO H H H NO2 540 403 NO2 H 1-Pyrrolidinyl-CO H H 538 404NO2 H N-Benzyl-N-MethylaminoCO— H H 588 405 H CF3 NO2 H H 509 406 H MeNO2 H H 455 407 H NO2 NO2 H H 486 408 Cl H NO2 H H 476 409 CF3 H NO2 H H509 410 Me H NO2 H H 455

EXAMPLE 411 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-{[(1,1′-biphenyl-2-ylamino)carbonothioyl]amino}-L-phenylalanine

[0334] The carboxylic acid was synthesized as follows: 200 μl of2-phenyl-phenylisothiocyanate was added to 30 mg of a resin having ananiline structure obtained by reducing nitro group in the same manner asthat of step 4 in Example 85. 500 μl of DCM was added thereto and thereaction was conducted at 25° C. for 24 hours. The reaction solution wasremoved and the resin was washed with DCM, NMP and DCM 3 times each. Thereaction solution was removed and the obtained resin was treated withtrifluoroacetic acid for 1 hour an then filtered out. The filtrate wasconcentrated to obtain the intended compound without the purification.

[0335] MS (ESI positive): 531

[0336] [C₂₉H₃₀N₄O₄S: 530]

EXAMPLES 412 TO 428

[0337] The carboxylic acids (general formula 1-11) were synthesized byusing a corresponding isocyanate or isothiocyanate in the same manner asthat of Example 411. In particular, compounds in Examples 423 to 425 inTable 2-10 were obtained by using 4-fluoro-3-nitrobenzene isocyanate andcompounds in Examples 426 to 428 were obtained by using2-fluoro-5-nitrobenzene isocyanate. In these Examples, after forming aurea, 500 μl of DMSO and 100 μl of a corresponding amine were addedthereto, and the reaction was conducted at 45° C. for 48 hours. Afterthe treatment with trifluoroacetic acid in the same manner as that ofExample 411 for 1 hour, the resin was filtered out. The filtrate wasconcentrated to obtain the intended compound without the purification.

[0338] L₂₅, L₂₆, L₂₇, L₂₈, L₂₉ and L₃₀ in Table 2-10 are each asubstituent in general formula (1-11) given below. TABLE 2-10 (1-11)

Example L25 L26 L27 L28 L29 L30 MS Found (MH+) 411 S H H H H ph 531 412S Cl H H H H 489 413 S Cl H H CF3 H 557 414 S CN H H H H 480 415 S Br HH Br H 613 416 S Cl H Cl H H 524, 526 417 S Et H H H Et 511 418 S MeO HMeO H H 515 419 S NO2 H H H H 500 420 O H CN H H H 464 421 O Cl H H H Cl508 422 O H H I H H 565 423 O H NO2 Et2N H H 555 424 O H NO21-Pyrrolidinyl H H 553 425 O H NO2 N-Benzyl-N-methylamino H H 603 426 OEt2N H H NO2 H 555 427 O 1-Pyrrolidinyl H H NO2 H 553 428 ON-Benzyl-N-methylamino H H NO2 H 603

EXAMPLE 429 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-[ethyl(2-nitrobenzyl)amino]-L-phenylalanine

[0339] The carboxylic acid was synthesized as follows: 2.24 g of2-nitrobenzenesulfonyl chloride was added to 1.3 g of a resin having ananiline structure obtained by reducing nitro group in the same manner asthat of step 4 in Example 85. Then the reaction was conducted in 2.3 mlof 2,6-lutidine and 30 ml of DCM at 25° C. for 48 hours. The reactionsolution was removed and the resin was washed with DCM, NMP and DCM 3times each. 200 μl of ethyl iodide, 600 mg of potassium carbonate and 1ml of NMP were added to 30 mg of the resin in the same manner as that ofExample 380. The obtained solution was shaken at 35° C. for 24 hours.The reaction solution was removed, and the resin was washed with DCM,NMP and DCM 3 times each. 200 μl of DBU, 400 μl of 2-mercaptoethanol and500 μl of NMP were added to 30 mg of the obtained resin, and the mixturewas shaken at room temperature for 24 hours. The reaction solution wasremoved, and the resin was washed with DCM, NMP and DCM 3 times each.200 μl of 2-nitrobenzyl bromide, 500 μl of diisopropylethylamine and 500μl of NMP were added to the resin and the reaction was conducted at 80°C. for 24 hours. The reaction solution was removed and the obtainedresin was washed with DCM, NMP and DCM 3 times each. The obtained resinwas treated with 100% trifluoroacetic acid for 1 hour an then filteredout. The filtrate was concentrated to obtain the intended compoundwithout the purification.

[0340] MS (ESI positive): 483

[0341] [C₂₅H₃₀N₄O₆: 482]

EXAMPLES 430 TO 444

[0342] The carboxylic acids (general formula 1-12) were synthesized byusing a corresponding bromide, chloride or iodide in the same manner asthat of Example 429. In Examples 430, 431, 432 and 441, the secondalkylation treatment in Example 429 was omitted.

[0343] L₃₁ and L₃₂ in Table 2-11 are each a substituent in generalformula (1-12) given below. TABLE 2-11 (1-12)

Example L31 L32 MS Found (MH+) 430 2-MePh H 536 431 3-NO2Ph H 476 4322,4-DiCF3Ph H 494 433 2-MePh Et 564 434 3-NO2Ph Et 504 435 2,4-DiCF3PhEt 522 436 2-MePh Allyl 576 437 3-NO2Ph Allyl 516 438 2,4-DiCF3Ph Allyl534 439 3-NO2Ph Tetrahydrofurfuryl 560 440 2,4-DiCF3PhTetrahydrofurfuryl 578 441 PhSCH2 H 456 442 PhSCH2 Et 484 443 PhSCH2Allyl 496 444 PhSCH2 Tetrahydrofurfuryl 540

EXAMPLE 445 Synthesis ofN-{2-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-ethylbutanoyl}-4-benzoyl-L-phenylalanine

[0344] 30 mg of the intermediate resin obtained in Example 449 wasshaken in DMF for 30 minutes and then taken out by the filtration. Theresin was treated in 300 μl of 20% solution of piperidine in DMF for 3minutes and then for 10 minutes. The resin was washed with DMF and DCMand then shaken in a solution of 36.5 mg of diethylmalonic acid, 106 μlof DIC and 93 mg of HOAt in 600 μl of NMP overnight. After washing withDMF and DCM, the resin was shaken in a solution (600 μl) of 41 mg of4-(4-hydroxyphenyl)piperazine, 31 mg of HOAt and 35 μl of DIC in NMPovernight. After washing with DMF, DCM, methanol and diethyl ether, theresin was shaken in 300 μl of 95% aqueous TFA solution for 1 hour. Afterthe filtration, the filtrate was dried under reduced pressure, and theproduct was taken by HPLC and freeze-dried to obtain 1.7 mg of theintended compound in the form of a white solid.

[0345] MS (ESI positive): 572

[0346] [C₃₃H₃₇N₃O₆: 571]

EXAMPLE 446 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-(4-phenyl-1,3-thiazole-2-yl)-L-phenylalanine

[0347] A resin having nitryl group was synthesized in the same manner asthat of Example 85 except that Fmoc-Phe(4—CN)—OH was used in step 1 and1,1-cyclopropanedicarboxylic acid and dimethylamine were used in step 3.1 mg of O,O-diethyl dithiophosphate and then 5 ml of THF/water (4/1)were added to 200 mg of the obtained resin and the reaction wasconducted at 77° C. for 24 hours. The reaction solution was removed, andthe resin was washed with DCM, NMP and DCM 3 times each. 500 μl ofα-bromoacetophenone and 1 ml of NMP were added to 30 mg of the obtainedresin, and the resultant mixture was shaken at 77° C. for 24 hours. Thereaction solution was removed, and the resin was washed withdichloromethane, NMP and dichloromethane 3 times each. The obtainedsolution was concentrated and purified by the reversed-phase HPLC(SYMMETRY 19*50 mm, mobile phase: water/acetonitrile each containing0.1% of TFA) to obtain 2.0 mg of the intended compound.

[0348] MS (ESI positive): 464

[0349] [C₂₅H₂₅N₈O₄S: 463]

EXAMPLE 447 Synthesis of N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-4-(8H-indeno [1,2-d][1,3]thiazole-2-yl)-L-phenylalanine

[0350] A resin having nitryl group was synthesized in the same manner asthat of Example 85 except that Fmoc-Phe(4—CN)—OH was used in step 1 and1,1-cyclopropanedicarboxylic acid and dimethylamine were used in step 3.1 mg of O,O-diethyl dithiophosphate and then 5 ml of THF/water (4/1)were added to 200 mg of the obtained resin and the reaction wasconducted at 77° C. for 24 hours. The reaction solution was removed, andthe resin was washed with dichloromethane, NMP and dichloromethane 3times each. 500 μl of 2-bromo-1-indanone and 1 ml of NMP were added to30 mg of the obtained resin, and the resultant solution was shaken at77° C. for 24 hours. The reaction solution was removed, and the resinwas washed with dichloromethane, NMP and dichloromethane 3 times each.The obtained solution was concentrated and purified by thereversed-phase HPLC (SYMMETRY 19*50 mm, mobile phase: water/acetonitrileeach containing 0.1% of TFA) to obtain 2.1 mg of the intended compound.

[0351] MS (ESI positive): 476

[0352] [C₂₆H₂₅N₃O₄S: 475]

EXAMPLE 448 Synthesis ofN-(2-dimethylaminocarbonyl-2-methylpropanoyl)-O-phenyl-L-tyrosine

[0353] 4.19 g of N-Boc Tyrosine Methyl ester, 2.58 g of copper (I)acetate, 3.46 g of phenylboric acid, 135 ml of DCM, 3 g of molecularsieve 4A and 5.73 ml of pyridine were fed into a 200 ml flask. Afterstirring at room temperature for 4 days, 1 g of molecular sieve 4A, 1.73g of phenylboric acid, 1.29 g of copper (I) acetate and 2.86 ml ofpyridine were added to the mixture, and the mixture were stirred at roomtemperature overnight. The reaction mixture was filtered through Celite,concentrated and purified with a medium pressure column to obtain 2.77 gof methyl ester of N-Boc-O-phenyltyrosine in the form of a colorless,viscous liquid.

[0354] The compound obtained as described above was added to 39 ml of 4M solution of hydrogen chloride in ethyl acetate. They were stirred atroom temperature for 4 hours and then concentrated to obtain 2.16 g ofhydrochloride of methyl ester of N-Boc-O-phenyltyrosine in the form of awhite solid.

[0355] 29 mg of this compound, 36 mg of WSC HCl, 16 ml of HOBt·H₂O, 15mg of dimethylmalonic acid monodimethylamide, 1 ml of DCM and 13 μl oftriethylamine were mixed together, and the mixture was stirred at roomtemperature overnight. The reaction solution was washed with 1 M aqueoushydrochloric acid solution, saturated aqueous sodium hydrogencarbonatesolution and water. The product was dried over magnesium sulfate,concentrated and purified by TLC to obtain 19 mg of a white solid.

[0356] 1 ml of THF, 1 ml of methanol, 2.3 mg of lithium hydroxidemonohydrate and 0.5 ml of water were added to the obtained compound, andthe mixture stirred at room temperature for 3 hours and thenconcentrated under reduced pressure. The product was dissolved in waterand washed with DCM. Ethyl acetate was added to the aqueous layer. Afteradding 55 μl of 1 M aqueous hydrochloric acid solution, the obtainedmixture was stirred and then separated into layers. The organic layerwas dried over brine and then over magnesium sulfate, and concentratedunder reduced pressure to obtain 3.5 mg of the intended compound in theform of an almond-colored solid.

[0357] MS (ESI positive): 399

[0358] [C₂₇H₃₃N₅O₇: 398]

EXAMPLE 449 Synthesis ofN-[4-(4-hydroxyphenyl)piperazino-carbonylcyclopropane-1-ylcarbonyl]-4-benzoyl-L-phenylalanine

[0359] 430 mg of Wang resin was immersed in DMF for 1.5 hours. DMF wasremoved by the filtration, and the resin was shaken in a solution of 128μl of DIC, 416 mg of N-Fmoc-4-benzoylphenylalanine H₂O and 4 mg of DMAPin 3.6 ml of DMF at room temperature for 4 hours. The resin was washedwith DMF and DCM, and then shaken in a solution of 309 μl of aceticanhydride and 264 μl of pyridine in 3.3 ml of DMF for 2 hours. Afterwashing with DMF, DCM, methanol and diethyl ether and drying underreduced pressure, 530 mg of an intermediate resin was obtained.

[0360] 30 mg of the intermediate resin was shaken in DMF for 30 minutesand then filtered. The resin was treated with 300 μM 1 of 20% solutionof piperidine in DMF for 3 minutes and then for 10 minutes. Afterwashing with DMF and DCM, a solution of 29 mg of1,1-cyclopropanedicarboxylic acid, 106 μl of DEC and 93 mg of HOAt in600 μl of NMP was added to the product and they were shaken overnight.After washing with DMF and DCM, 41 mg of 4-(4-hydroxyphenyl)piperazine,31 mg of HOAt, 35μl of DIC and 600 μl of NMP were added to the resin andthey were shaken overnight. After washing with DMF, DCM, methanol anddiethyl ether followed by the shaking in 300 μl of 95% aqueous TFAsolution for 1 hour, the reaction mixture was filtered. The filtrate wasdried under reduced pressure and the product was purified by HPLC andthen freeze-dried to obtain 0.04 mg of the intended compound in the formof a white solid.

[0361] MS (ESI positive): 542

[0362] [C₃₁H₃₁N₃O₆: 541]

EXAMPLE 485 Synthesis ofN-[2-ethyl-2-(pyrrolidine-1-ylcarbonyl)-butanoyl]-4-benzoyl-L-phenylalanine

[0363] The intermediate resin obtained in Example 449 was shaken in DMFfor 30 minutes and then filtered. The resin was treated with 20%solution of piperidine in DMF for 3 minutes and then for 10 minutes.After washing with DMF and DCM, the resin was shaken in a solution ofdiethylmalonic acid, DIC and HOAt in NMP overnight. The resin was washedwith DMF and DCM and then shaken in a solution of pyrrolidine, HOAt andDIC in NMP overnight. After washing with DMF, DCM, methanol and diethylether followed by the shaking in 95% aqueous TFA solution for 1 hour,the reaction mixture was filtered. The filtrate was dried under reducedpressure and the product was purified by HPLC and then freeze-dried toobtain the intended compound in the form of a white solid.

[0364] MS (ESI positive): 465

[0365] [C₂₇H₃₂N₂O₅: 464]

EXAMPLE 486 Synthesis ofN-[2-ethyl-2-(phenylsulfonyl)butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine

[0366] Step 1 Synthesis of 2-ethyl-2-(phenylsulfonyl)Butanoic Acid:

[0367] Methyl phenylsulfonylacetate (0.64 ml, 4.0 mmol) was diluted withDMF (5 ml). Sodium hydride (384 mg, 16 mmol) and ethyl bromide (1.19 ml,16 mmol) were added thereto under argon atmosphere. The mixture wasstirred at room temperature overnight. Water was added to the reactionmixture under cooling with ice to terminate the reaction. After theextraction with ethyl acetate (10 ml×3), the organic layers werecombined together, dried and concentrated under reduced pressure. Theresidue was purified by the silica gel column chromatography (hexane,hexane/ethyl acetate, 100/1) to obtain an intermediate product. Theintermediate product (532 mg, 1.97 mmol) was dissolved in THF (4 ml).Water (70.9 μl, 3.84 mmol) and tBuOK (1.77 g, 15.8 mmol) were added tothe obtained solution. The reaction mixture was stirred at roomtemperature for 4 days. Additional water (35.5 μl, 1.97 mmol) and tBuOK(1.55 g, 13.8 mmol) were added to the obtained solution. After stirringat room temperature for 9 days, the reaction mixture was diluted withDCM (10 ml). The resultant mixture was extracted with water (10 ml). pHof the aqueous layer was adjusted to 2. After the extraction with DCM(10 ml×3), the organic layers were combined together, dried andconcentrated under reduced pressure to quantitatively obtain 481 mg ofthe intended compound.

[0368]¹H-NMR (CDCl₃) δ=1.10(6H, t, J=7.4 Hz), 1.99-2.28(4H, m),7.52-7.74(3H, m), 7.85-7.93(2H, m)

[0369] Step 2

[0370] 30 mg of the resin obtained in Example 1 was added to a solutionof 2-ethyl-2-(phenylsulfonyl)butanoic acid, HOAt and DIC in DMF toconduct the reaction at room temperature for 20 hours. The reactionsolution was removed, and the resin was washed with DMF, methanol anddichloromethane 6 times each. The resin was then treated with 95%aqueous trifluoroacetic acid solution for 1 hour. The resin was taken bythe filtration and then washed with acetonitrile. The filtrates werecombined together and concentrated. After the purification by thereversed-phase HPLC [Inertsil ODS column, developer: water/acetonitrile(TFA 0.05%)], the intended compound was obtained.

[0371] MS (ESI positive): 578

[0372] [C₂₈H₂₉NO₆Cl₂S: 577]

EXAMPLE 487 Synthesis of N-[2-ethyl-2-(pyrrolidine-1-ylcarbonyl)butanoyl]-O-(2,6-dichlorobenzyl)-3,5-diiodo-L-tyrosine

[0373] Methyl ester of N-Boc-3,5-diiodo-L-tyrosine (50 mg) was dissolvedin 4 N solution (1 ml) of hydrochloric acid in dioxane, and the reactionwas conducted for 1 hour. The reaction solution was concentrated underreduced pressure, and the residue was dissolved in NMP (0.5 ml)/DIEA(0.012 ml). Separately, a solution (0.5 ml) of diethylmalonic acid (23mg), DIC (0.066 ml) and HOAt (58 mg) in NMP was prepared, and NMP-DIEAprepared as described above was added dropwise to the NMP solution. Thereaction was conducted for 2 hours, and then ethyl acetate was added tothe reaction solution. After washing with water and saturated aqueoussodium chloride solution, the product was dried and concentrated underreduced pressure. The white solid thus obtained was dissolved in NMP (1ml). Pyrrolidine (0.0054 ml) was added to the obtained solution, andthey were stirred for 16 hours. A small amount of water was added to thereaction mixture. After the extraction with dichloromethane/isopropanol(2/1, 30 ml, 3 times), the extract was dried and then concentrated underreduced pressure. The obtained yellow oil was dissolved in methanol(0.25 ml). 0.1 N aqueous LiOH solution was added to the obtainedsolution, and they were stirred for 5 hours. A small amount of water wasadded to the reaction mixture. After the extraction withdichloromethane/isopropanol (2/1, 30 ml, 3 times), the extract was driedand then concentrated under reduced pressure. The residue was purifiedby the reversed-phase HPLC [Waters Co., Symmetry C18 column (5 μM; 19 mmdiameter×50 mm), developer: water/acetonitrile (TFA 0.05%)] to obtainthe intended compound (0.4 mg).

[0374] MS (ESI positive): 787

[0375] [C₂₇H₃₂N₂O₅: 786]

TEST EXAMPLE

[0376] CAM Antagonist Activity (VCAM-1/α 4 β 1 Binding Assay):

[0377] The capacity of a test substance antagonistic to the binding ofcell strain Jurkat (ATCC TIB-152) of human T cells, known to expressintegrin α 4 β 1, to VCAM-1 was determined.

[0378] 100 μl/well of a solution (500 ng/ml) of recombinant human VCAM-1(R & D systems) solution diluted with buffer A (0.1 M NaHCO₃, pH 9.6)was added to a micro titer plate having 96 wells (Nunc Maxisorp). Afterthe incubation at 4° C. overnight, unbound VCAM-1 was removed by washingonce with PBS. After completion of the washing, a buffer (buffer B)obtained by diluting Block Ace® (Dainippon Pharmaceutical Co., Ltd.)with PBS to ¼ concentration was added in an amount of 150 μl/well. Afterthe incubation at room temperature for 1 hour, buffer B was removed andthe plate was washed with PBS once.

[0379] Jurkat cells were washed with Dulbecco modified Eagle medium(SIGMA, hereinafter referred to as “DMEM”) twice and then incubated inDMEM containing 10 μg/ml of Calcein-AM (Wako Pure Chemical Industries,Ltd.) at 37° C. in dark place for 30 minutes to label with fluorescence.The cells were again suspended in a binding buffer (20 mM HEPES, DMEMcontaining 0.1% BSA).

[0380] 50 μl of a test substance of various concentrations obtained bythe dilution with the binding buffer was added to the plate. Immediatelythereafter, 50 μl (final volume: 100 μl/well) of the fluorescent Jurkatcells (4×10⁶ cells/ml) were added thereto, and they were incubated atroom temperature for 30 minutes. After the shaking on a plate shaker(IKA MTS-4) at 800 rpm for 30 seconds, the solution was immediatelyremoved to remove the unbound cells. The fluorescence quantity of thebound cells remaining in the wells was determined with a fluorescentplate reader (Wallac 1420 ARVO multi-label counter) (filter excitationwave length: 485 nm, emission wave length: 535 nm). The fluorescentstrength thus obtained is proportional to the number of Jurkat cellsbound to VCAM-1 and remaining on the plate. The binding rate of eachtest material in various concentrations was determined while thefluorescent strength of the test material-free well was determined to be100%. The concentration IC₅₀ for the 50% binding inhibition wascalculated.

[0381] The obtained test results are shown in Table 3. The activitieswere classified into group A wherein IC₅₀ was 0.02 μmol/l or below,group B wherein IC₅₀ was higher than 0.02 μmol/l and not above 0.1μmol/l, group C wherein IC₅₀ was higher than 0.1 μmol/l and not above 2μmol/l, and group D wherein IC₅₀ was higher than 2 μmol/l and not above10 μmol/l.

TEST EXAMPLE VCAM Antagonistic Activity (VCAM-1/α 4 β 7 Binding Assay):

[0382] The capacity of a test substance antagonistic to the binding oflymphoma cell strain RPMI-8866 of human B cells, known to expressintegrin α 4 β 7, to VCAM-1 was determined.

[0383] 100 μl/well of a solution (500 ng/ml) of recombinant human VCAM-1(R & D systems) solution diluted with buffer A (0.1 M NaHCO₃, pH 9.6)was added to a micro titer plate having 96 wells (Nunc Maxisorp). Afterthe incubation at 4° C. overnight, unbound VCAM-1 was removed by washingonce with PBS. After completion of the washing, a buffer (buffer B)obtained by diluting Block Ace® (Dainippon Pharmaceutical Co., Ltd.)with PBS to ¼ concentration was added in an amount of 150 μl/well. Afterthe incubation at room temperature for 1 hour, buffer B was removed andthe plate was washed with PBS once.

[0384] RPMI-8866 cells were incubated in Dulbecco modified Eagle mediumcontaining 10 μg/ml of Calcein-AM (Wako Pure Chemical Industries, Ltd.)(SIGMA, hereinafter referred to as “DMEM”) at 37° C. for 30 minutes tolabel with fluorescence. The cells were again suspended in a bindingbuffer (20 mM HEPES, DMEM containing 0.1% BSA) containing 4 mM of MnCl₂.

[0385] 50 μl of a test substance of various concentrations obtained bythe dilution with the binding buffer was added to the plate. Immediatelythereafter, 50 μl (final volume: 100 μl/well) of the fluorescentRPMI-8866 cells (4×10⁶ cells/ml) were added thereto, and they wereincubated at room temperature for 30 minutes. After the shaking on aplate shaker (IKA MTS-4) at 800 rpm for 30 seconds, the solution wasimmediately removed to remove the unbound cells. The fluorescencequantity of the bound cells remaining in the wells was determined with afluorescent plate reader (Wallac 1420 ARVO multi-label counter) (filterexcitation wave length: 485 nm, emission wave length: 535 nm). Thefluorescent strength thus obtained is proportional to the number ofRPMI-8866 cells bound to VCAM-1 and remaining on the plate. The bindingrate of each test material in various concentrations was determinedwhile the fluorescent strength of the test material-free well wasdetermined to be 100%. The concentration IC₅₀ for the 50% bindinginhibition was calculated.

[0386] The obtained test results are shown in Table 3. The activitieswere classified into group A wherein IC₅₀ was 0.02 μmol/l or below,group B wherein IC₅₀ was higher than 0.02 μmol/l and not above 0.1μmol/l, group C wherein IC₅₀ was higher than 0.1 μmol/l and not above 2μmol/l, and group D wherein IC₅₀ was higher than 2 μmol/l and not above10 μmol/l. TABLE 3 Results of the determination of VCAM antagonisticactivity (IC50, umol/L): 10 ≧ D > 2.0 ≧ C > 0.1 ≧ B > 0.02 ≧ A Example α4 β 7 α 4 β 1 2 B C 3 A C 5 C C 6 C D 7 C C 8 C C 9 C C 17 C C 21 C D 23C D 29 C C 32 B C 33 B C 34 B C 35 A B 36 B C 37 B D 38 C C 39 B C 40 BC 41 B C 42 B C 43 A C 44 A C 45 B C 46 A C 47 A C 48 B C 49 B C 50 B C51 B C 52 A B 53 A C 54 A B 55 A B 56 A C 57 B C 58 C C 59 B C 60 C C 61B C 62 B C 63 B C 64 B C 65 A C 66 B C 67 B C 68 A B 69 A C 70 A B 71 AB 72 A B 73 A B 74 A C 75 A C 76 A C 77 A C 78 A C 79 A C 80 A C 81 A C82 A B 83 A B 84 A C 85 A C 86 B C 87 B C 88 C C 89 C C 90 B C 91 A A 92A B 93 A C 94 A B 95 A B 96 A B 97 A B 98 A B 99 B B 100 B C 101 B C 102A C 103 B C 104 B C 105 B C 463 C C 464 B C 465 A C 466 A B 467 A C 468A C 472 C D 477 A B 478 A B 479 A B 480 A B 481 A B 482 A C 483 A B 484A B

[0387] It is thus apparent that the new phenylalanine derivativesexhibited an excellent α-integrin inhibiting activity.

[0388] Since the new phenylalanine derivatives of the present inventionhave excellent α-integrin inhibiting activity, the present inventionprovides a therapeutic agent or preventive agent for diseases in which α4 integrin-depending adhesion process participates in the pathology,such as inflammatory diseases, rheumatoid arthritis, inflammatory boweldiseases, systemic erythematodes, multiple sclerosis, Sjogren'ssyndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases,arterial sclerosis, restenosis, tumor proliferation, tumor metastasisand transplantation rejection.

What is claimed is:
 1. Phenylalanine derivatives of the followinggeneral formula (1) and pharmaceutically acceptable salts thereof:

wherein X represents an interatomic bond, —O—, —O—SO₂—, —NR¹—,—NR¹—C(═O)—, —NR¹—SO₂—, —NR¹—C(═O)—NH—, —NR¹—C(═S)—NH— or —C(═O)—wherein R¹ represents a hydrogen atom, a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a lower alkyl group substitutedwith a cycloalkyl group(s) which may contain a hetero atom(s) in thering thereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s), Y represents—C(═O)—, —S(═O)— or —SO₂—, Z represents —C(═O)—, —S(═O)— or —SO₂—, Arepresents a group of the following general formula (2), a group of anyof the following general formulae (2-1) to (2-5), a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with a group of general formula (2), a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s) or a lower alkynyl groupsubstituted with a heteroaryl group(s):

wherein R², R³, R⁴, R⁵ and R⁶ may be the same or different from oneanother, and each represents a hydrogen atom, a halogen atom, a hydroxylgroup, a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkoxyl group, a lower alkoxyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkoxyl group substituted with an aryl group(s), alower alkoxyl group substituted with a heteroaryl group(s), acycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group:

wherein Arm represents benzene ring or an aromatic ring containing 1, 2,3 or 4 hetero atoms selected from among oxygen, sulfur and nitrogenatoms, R⁹ represents an oxygen atom, a substituted or unsubstitutedimino group or sulfur atom, R¹⁰, R¹¹, R¹² and R¹³ may be the same ordifferent from one another and each represents a hydrogen atom, ahalogen atom, hydroxyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with an aryl group(s), a lower alkyl group substituted witha heteroaryl group(s), a lower alkoxyl group, a lower alkoxyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkoxyl group substituted with anaryl group(s), a lower alkoxyl group substituted with a heteroarylgroup(s), a cycloalkyloxy group which may contain a hetero atom(s) inthe ring thereof, an aryloxy group, a heteroaryloxy group, ahydroxy-lower alkyl group, a hydroxy-lower alkenyl group, ahydroxy-lower alkoxyl group, a halogeno-lower alkyl group, ahalogeno-lower alkoxyl group, a halogeno-lower alkenyl group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkanoyl group, an aroyl group, a loweralkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ may be the same ordifferent from one another and each represents a hydrogen atom, ahalogen atom, hydroxyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with an aryl group(s), a lower alkyl group substituted witha heteroaryl group(s), a lower alkoxyl group, a lower alkoxyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkoxyl group substituted with anaryl group(s), an alkoxyl group substituted with a heteroaryl group(s),a cycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group, R²⁰ representsan oxygen atom, a substituted or unsubstituted imino group or sulfuratom, R¹⁸ and R¹⁹ may be the same or different from each other and eachrepresents a hydrogen atom, a lower alkyl group, a lower alkenyl group,a lower alkynyl group, a cycloalkyl group which may contain a heteroatom(s) in the ring thereof, an aryl group, a heteroaryl group, a loweralkyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkyl group substituted withan aryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group, a halogeno-lower alkenyl group,a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group or asubstituted or unsubstituted amino-lower alkyl group, or R¹⁸ and R¹⁹ maybe bonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms, and the substituents of the ring includehydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, R²³ represents an oxygenatom, a substituted or unsubstituted imino group or sulfur atom, R²¹ andR²² may be the same or different from each other and each represent ahydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkoxyl group, a loweralkoxyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkoxyl group substitutedwith an aryl group(s), a lower alkoxyl group substituted with aheteroaryl group(s), a cycloalkyloxy group which may contain a heteroatom(s) in the ring thereof, an aryloxy group, a heteroaryloxy group, ahydroxy-lower alkyl group, a hydroxy-lower alkenyl group, ahydroxy-lower alkoxyl group, a halogeno-lower alkyl group, ahalogeno-lower alkoxyl group, a halogeno-lower alkenyl group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkanoyl group, an aroyl group, a loweralkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group, R²⁴ and R²⁵ may be the same or differentfrom each other and each represents a hydrogen atom, a halogen atom,hydroxyl group, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkoxyl group, a lower alkoxyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkoxyl group substituted with an aryl group(s), alower alkoxyl group substituted with a heteroaryl group(s), acycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group, B represents ahydroxyl group, a lower alkoxyl group or a hydroxyamino group, Crepresents a hydrogen atom, a lower alkyl group, a lower alkenyl group,a lower alkynyl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s) or a lower alkyl groupsubstituted with a heteroaryl group(s), D and E may be the same ordifferent from each other and each represent a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s), a lower alkynyl groupsubstituted with a heteroaryl group(s), a halogeno-lower alkyl group, alower alkoxy-lower alkyl group, a hydroxy-lower alkyl group, a loweralkylthio-lower alkyl group, a mercapto-lower alkyl group or asubstituted or unsubstituted amino-lower alkyl group, or D and E may bebonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms, F and G may be the same or different from eachother and each represents a hydrogen atom, a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s), a lower alkynyl groupsubstituted with a heteroaryl group(s), a halogeno-lower alkyl group ora hydroxy-lower alkyl group, or F and G may be bonded together to form aring which may contain one or two oxygen, nitrogen or sulfur atoms, nrepresents an integer of 0 to 2, K represents OR⁷, NR⁷R⁸, NHNR⁷R⁸,NR⁷NHR⁸, SR⁷ or R⁷ wherein R⁷ and R⁸ may be the same or different fromeach other and each represents a hydrogen atom, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s), a lower alkynyl groupsubstituted with a heteroaryl group(s), a halogeno-lower alkyl group, ahalogeno-lower alkenyl group, a hydroxy-lower alkyl group, ahydroxy-lower alkenyl group or a substituted or unsubstitutedamino-lower alkyl group, or R⁷ and R⁸ may be bonded together to form aring which may contain one or two oxygen, nitrogen or sulfur atoms andthe substituents of the ring include hydrogen atom, a halogen atom,hydroxyl group, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkanoyl group, an aroyl group, a halogeno-loweralkanoyl group, a lower alkyloxy group, nitro group, cyano group, asubstituted or unsubstituted amino group, carboxyl group, a loweralkyloxycarbonyl group, a substituted or unsubstituted carbamoyl group,a lower alkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group, and J and J′ may be the same or differentfrom each other and each represents a hydrogen atom, a halogen atom, alower alkyl group, a lower alkyloxy group or nitro group.
 2. Thephenylalanine derivatives and pharmaceutically acceptable salts thereofaccording to claim 1, wherein X represents an interatomic bond or agroup of the formula: —O—, —O—SO₂—, —NR¹—, —NR¹—C(═O)—, —NR¹—SO₂— or—C(═O)—, Y represents a group of the formula: —C(═O)—, Z represents agroup of the formula: —C(═O)— or —O—SO₂—, A represents a group ofgeneral formula (2), a group of any of general formulae (2-1) to (2-5),a lower alkyl group, a lower alkenyl group, a lower alkynyl group, acycloalkyl group which may contain a hetero atom(s) in the ring thereof,an aryl group, a heteroaryl group, a lower alkyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with a group of general formula(2), a lower alkyl group substituted with an aryl group(s) or a loweralkyl group substituted with a heteroaryl group(s), B represents ahydroxyl group or a lower alkoxyl group, C represents a hydrogen atom ora lower alkyl group, D and E may be the same or different and eachrepresents a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with an aryl group(s), alower alkenyl group substituted with a heteroaryl group(s), ahalogeno-lower alkyl group, a lower alkoxy-lower alkyl group, ahydroxy-lower alkyl group, a lower alkylthio-lower alkyl group, amercapto-lower alkyl group or a substituted or unsubstituted amino-loweralkyl group, or D and E may be bonded together to form a ring which maycontain one or two oxygen, nitrogen or sulfur atoms, and n represents aninteger of
 0. 3. The phenylalanine derivatives and pharmaceuticallyacceptable salts thereof according to claim 1, wherein X represents aninteratomic bond or a group of the formula: —O—, —O—SO₂—, —NR¹—,—NR¹—C(═O)—, —NR¹—SO₂— or —C(═O)—, Y represents a group of the formula:—C(═O)—, Z represents a group of the formula: —C(═O)—, A represents agroup of general formula (2), a group of any of general formulae (2-1)to (2-5), a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with agroup of general formula (2), a lower alkyl group substituted with anaryl group(s) or a lower alkyl group substituted with a heteroarylgroup(s), B represents a hydroxyl group, C represents a hydrogen atom, Dand E may be the same or different and each represents a lower alkylgroup, or D and E may be bonded together to form a ring which maycontain one or two oxygen, nitrogen or sulfur atoms, J and J′ eachrepresent hydrogen atom, and n represents an integer of
 0. 4. Thephenylalanine derivatives and pharmaceutically acceptable salts thereofaccording to claim 3, wherein A represents a group of general formula(2), a group of any of general formulae (2-1) to (2-5), a lower alkylgroup substituted with a group of general formula (2), a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, or aheteroaryl group.
 5. The phenylalanine derivatives and pharmaceuticallyacceptable salts thereof according to claim 3, wherein K representsNR⁷R⁸ or NHNR⁷R⁸, R⁷ and R⁸ may be the same or different from each otherand each represents a hydrogen atom, a lower alkyl group, a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, an arylgroup, a heteroaryl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s), or R⁷ and R⁸may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms; and the substituents of the ringinclude a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a cycloalkyl groupwhich may contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkoxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl groupand a substituted or unsubstituted sulfamoyl group.
 6. The phenylalaninederivatives and pharmaceutically acceptable salts thereof according toclaim 1, wherein X represents a group of the formula: —O—, Y representsa group of the formula: —C(═O)—, Z represents a group of the formula:—C(═O)—, A represents a lower alkyl group substituted with a group ofgeneral formula (2), R², R³, R⁴, R⁵ and R⁶ may be the same or differentfrom one another, and each represents a hydrogen atom or a halogen atom,B represents a hydroxyl group, C represents a hydrogen atom, D and E maybe the same or different and each represents a lower alkyl group, or Dand E may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms, n represents an integer of 0, Krepresents NR⁷R⁸ or NHNR⁷R⁸, R⁷ and R⁸ may be the same or different fromeach other and each represents a hydrogen atom, a lower alkyl group, acycloalkyl group which may contain a hetero atom(s) in the ring thereof,an aryl group, a heteroaryl group, a lower alkyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s), or R⁷ and R⁸may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms; and the substituents of the ringinclude a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a cycloalkyl groupwhich may contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and J and J′ eachrepresents a hydrogen atom.
 7. The phenylalanine derivatives andpharmaceutically acceptable salts thereof according to claim 6, whereinK represents a group of the formula: NR⁷R⁸
 8. The phenylalaninederivatives and pharmaceutically acceptable salts thereof according toclaim 7, wherein R⁷ and R⁸ are bonded together to form a ring.
 9. Thephenylalanine derivatives and pharmaceutically acceptable salts thereofaccording to claim 1, wherein X represents a group of the formula:—NR¹—C(═O)—, Y represents a group of the formula: —C(═O)—, Z representsa group of the formula: —C(═O)—, A represents a group of general formula(2) wherein R², R¹, R⁴, R⁵ and R⁶ may be the same or different from oneanother, and each represents a hydrogen atom or a halogen atom, acycloalkyl group which may contain a hetero atom(s) in the ring thereofor a heteroaryl group, B represents a hydroxyl group, C represents ahydrogen atom, D and E may be the same or different and each representsa lower alkyl group, or D and E may be bonded together to form a ringwhich may contain one or two oxygen, nitrogen or sulfur atoms, nrepresents an integer of 0, K represents NR⁷R⁸ or NHNR⁷R⁸, R⁷ and R⁸ maybe the same or different from each other and each represents a hydrogenatom, a lower alkyl group, a cycloalkyl group which may contain a heteroatom(s) in the ring thereof, an aryl group, a heteroaryl group, a loweralkyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkyl group substituted withan aryl group(s) or a lower alkyl group substituted with a heteroarylgroup(s), or R⁷ and R⁸ may be bonded together to form a ring which maycontain one or two oxygen, nitrogen or sulfur atoms; and thesubstituents of the ring include hydrogen atom, a halogen atom, hydroxylgroup, a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkanoyl group, an aroyl group, a halogeno-loweralkanoyl group, a lower alkyloxy group, nitro group, cyano group, asubstituted or unsubstituted amino group, carboxyl group, a loweralkyloxycarbonyl group, a substituted or unsubstituted carbamoyl group,a lower alkylthio group, a lower alkylsulfonyl group or a substituted orunsubstituted sulfamoyl group, and J and J′ each represents a hydrogenatom.
 10. The phenylalanine derivatives and pharmaceutically acceptablesalts thereof according to claim 9, wherein K represents NR⁷R⁸.
 11. Thephenylalanine derivatives and pharmaceutically acceptable salts thereofaccording to claim 10, wherein R⁷ and R⁸ are bonded together to form aring.
 12. The phenylalanine derivatives and pharmaceutically acceptablesalts thereof according to claim 1, wherein X represents an interatomicbond, Y represents a group of the formula: —C(═O)—, Z represents a groupof the formula: —C(═O)—, A represents a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof or a heteroaryl group, Brepresents a hydroxyl group, C represents a hydrogen atom, D and E maybe the same or different and each represents a lower alkyl group, or Dand E may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms, n represents an integer of 0, Krepresents NR⁷R⁸, R⁷ and R⁸ may be the same or different from each otherand each represents a hydrogen atom, a lower alkyl group, a cycloalkylgroup which may contain a hetero atom(s) in the ring thereof, an arylgroup, a heteroaryl group, a lower alkyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s), or R⁷ and R⁸may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms; and the substituents of the ringinclude a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a cycloalkyl groupwhich may contain a hetero atom in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and J and J′ eachrepresents a hydrogen atom.
 13. The phenylalanine derivatives andpharmaceutically acceptable salts thereof according to claim 1, whereinA is represented by any of formulae (2-1) to (2-5).
 14. Thephenylalanine derivatives and pharmaceutically acceptable salts thereofaccording to claim 13, wherein A is represented by formula (2-1). 15.The following compounds and pharmaceutically acceptable salts thereofaccording to claim 1:


16. Phenylalanine derivatives of the following formulae andpharmaceutically acceptable salts thereof:


17. Phenylalanine derivatives of the following general formula (1) andpharmaceutically acceptable salts thereof:

wherein X represents an interatomic bond, —O—, —O—SO₂—, —NR¹—,—NR¹—C(═O)—, —NR¹—SO₂—, —NR¹—C(═O)—NH— or —NR¹—C(═S)—NH— wherein R¹represents a hydrogen atom, a lower alkyl group, a lower alkenyl group,a lower alkynyl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s) or a lower alkyl groupsubstituted with a heteroaryl group(s), Y represents —C(═O)—, —S(═O)— or—SO₂—, Z represents —C(═O)—, —S(═O)— or —SO₂—, A represents a group ofthe following general formula (2), a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a cycloalkyl group which may contain ahetero atom(s) in the ring thereof, an aryl group, a heteroaryl group, alower alkyl group substituted with a cycloalkyl group(s) which maycontain a hetero atom(s) in the ring thereof, a lower alkyl groupsubstituted with a group of general formula (2), a lower alkyl groupsubstituted with an aryl group(s), a lower alkyl group substituted witha heteroaryl group(s), a lower alkenyl group substituted with acycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkenyl group substituted with an aryl group(s), alower alkenyl group substituted with a heteroaryl group(s), a loweralkynyl group substituted with a cycloalkyl group(s) which may contain ahetero atom(s) in the ring thereof, a lower alkynyl group substitutedwith an aryl group(s) or a lower alkynyl group substituted with aheteroaryl group(s):

wherein R², R³, R⁴, R⁵ and R⁶ may be the same or different from oneanother, and each represents a hydrogen atom, a halogen atom, a hydroxylgroup, a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkoxyl group, a lower alkoxyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkoxyl group substituted with an aryl group(s), alower alkoxyl group substituted with a heteroaryl group(s), acycloalkyloxy group which may contain a hetero atom(s) in the ringthereof, an aryloxy group, a heteroaryloxy group, a hydroxy-lower alkylgroup, a hydroxy-lower alkenyl group, a hydroxy-lower alkoxyl group, ahalogeno-lower alkyl group, a halogeno-lower alkoxyl group, ahalogeno-lower alkenyl group, nitro group, cyano group, a substituted orunsubstituted amino group, a carboxyl group, a lower alkyloxycarbonylgroup, a substituted or unsubstituted carbamoyl group, a lower alkanoylgroup, an aroyl group, a lower alkylthio group, a lower alkylsulfonylgroup or a substituted or unsubstituted sulfamoyl group, B represents ahydroxyl group, a lower alkoxyl group or a hydroxyamino group, Crepresents a hydrogen atom, a lower alkyl group, a lower alkenyl group,a lower alkynyl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s) or a lower alkyl groupsubstituted with a heteroaryl group(s), D and E may be the same ordifferent from each other and each represents a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkenyl group substituted with anaryl group(s), a lower alkenyl group substituted with a heteroarylgroup(s), a lower alkynyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkynylgroup substituted with an aryl group(s), a lower alkynyl groupsubstituted with a heteroaryl group(s), a halogeno-lower alkyl group ora hydroxy-lower alkyl group, or D and E may be bonded together to form aring which may contain one or two oxygen, nitrogen or sulfur atoms, Fand G may be the same or different from one another and each representsa hydrogen atom, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group or a hydroxy-lower alkyl group,or F and G may be bonded together to form a ring which may contain oneor two oxygen, nitrogen or sulfur atoms, n represents an integer of 0 to2, K represents OR⁷, NR⁷R⁸, NHNR⁷R⁸, NR⁷NHR⁸, SR⁷ or R⁷ wherein R⁷ andR⁸ may be the same or different from each other and each represents ahydrogen atom, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a cycloalkyl group which may contain a hetero atom(s) inthe ring thereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with anaryl group(s), a lower alkyl group substituted with a heteroarylgroup(s), a lower alkenyl group substituted with a cycloalkyl group(s)which may contain a hetero atom(s) in the ring thereof, a lower alkenylgroup substituted with an aryl group(s), a lower alkenyl groupsubstituted with a heteroaryl group(s), a lower alkynyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkynyl group substituted with anaryl group(s), a lower alkynyl group substituted with a heteroarylgroup(s), a halogeno-lower alkyl group, a halogeno-lower alkenyl group,a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group or asubstituted or unsubstituted amino-lower alkyl group, or R⁷ and R⁸ maybe bonded together to form a ring which may contain one or two oxygen,nitrogen or sulfur atoms; and the substituents of the ring include ahydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group, alower alkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and J and J′ may be thesame or different from each other and each represents a hydrogen atom, ahalogen atom, a lower alkyl group, a lower alkyloxy group or nitrogroup.
 18. The phenylalanine derivatives and pharmaceutically acceptablesalts thereof according to claim 17, wherein X represents an interatomicbond or a group of the formula: —O—, —O—SO₂—, —NR¹—, —NR¹—C(═O)— or—NR¹—SO₂—, Y represents a group of the formula: —C(═O)—, Z represents agroup of the formula: —C(═O)— or —SO₂—, A represents a group of generalformula (2), a lower alkyl group, a lower alkenyl group, a lower alkynylgroup, a cycloalkyl group which may contain a hetero atom(s) in the ringthereof, an aryl group, a heteroaryl group, a lower alkyl groupsubstituted with a cycloalkyl group(s) which may contain a heteroatom(s) in the ring thereof, a lower alkyl group substituted with agroup of general formula (2), a lower alkyl group substituted with anaryl group(s) or a lower alkyl group substituted with a heteroarylgroup(s), B represents a hydroxyl group or a lower alkoxyl group, Crepresents a hydrogen atom or a lower alkyl group, D and E may be thesame or different and each represents a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a cycloalkyl group which maycontain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkenyl groupsubstituted with an aryl group(s), a lower alkenyl group substitutedwith a heteroaryl group(s), a halogeno-lower alkyl group or ahydroxy-lower alkyl group, or D and E may be bonded together to form aring which may contain one or two oxygen, nitrogen or sulfur atoms, andn represents an integer of
 0. 19. The phenylalanine derivatives andpharmaceutically acceptable salts thereof according to claim 17, whereinX represents a group of the formula: —O—, Y represents a group of theformula: —C(═O)—, Z represents a group of the formula: —C(═O)—, Arepresents a lower alkyl group substituted with a group of generalformula (2), R², R³, R⁴, R⁵ and R⁶ may be the same or different from oneanother, and each represents a hydrogen atom or a halogen atom, Brepresents a hydroxyl group, C represents a hydrogen atom, D and E maybe the same or different and each represents a lower alkyl group, or Dand E may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms, n represents an integer of 0, Krepresents NR⁷R⁸ or NHNR⁷R⁸, R⁷ and R⁸ may be the same or different fromeach other and each represents a hydrogen atom, a lower alkyl group, acycloalkyl group which may contain a hetero atom(s) in the ring thereof,an aryl group, a heteroaryl group, a lower alkyl group substituted witha cycloalkyl group(s) which may contain a hetero atom(s) in the ringthereof, a lower alkyl group substituted with an aryl group(s) or alower alkyl group substituted with a heteroaryl group(s), or R⁷ and R⁸may be bonded together to form a ring which may contain one or twooxygen, nitrogen or sulfur atoms; and the substituents of the ringinclude a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a cycloalkyl groupwhich may contain a hetero atom(s) in the ring thereof, an aryl group, aheteroaryl group, a lower alkyl group substituted with a cycloalkylgroup(s) which may contain a hetero atom(s) in the ring thereof, a loweralkyl group substituted with an aryl group(s), a lower alkyl groupsubstituted with a heteroaryl group(s), a lower alkanoyl group, an aroylgroup, a halogeno-lower alkanoyl group, a lower alkyloxy group, nitrogroup, cyano group, a substituted or unsubstituted amino group, carboxylgroup, a lower alkyloxycarbonyl group, a substituted or unsubstitutedcarbamoyl group, a lower alkylthio group, a lower alkylsulfonyl group ora substituted or unsubstituted sulfamoyl group, and J and J′ eachrepresent a hydrogen atom.
 20. The following compounds andpharmaceutically acceptable salts thereof according to claim 17:N-[2-(N,N-dimethylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(N,N-diethylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(N,N-dimethylaminocarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(N,N-diethylaminocarbonyl)-2-methyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[1-(N,N-dimethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[1-(N,N-diethylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(piperidine-1-ylcarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(piperidine-1-ylcarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)L-tyrosine;N-[1-(piperidine-1-ylcarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(N-methyl-N-phenylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(N-methyl-N-phenylaminocarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[1-(N-methyl-N-phenylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(4-hydroxyphenylaminocarbonyl)-2-methyl-propanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[2-(4-hydroxyphenylaminocarbonyl)-2-ethyl-butanoyl]-O-(2,6-dichlorobenzyl)-L-tyrosine;N-[1-(4-hydroxyphenylaminocarbonyl)cyclopropane-1-ylcarbonyl]-O-(2,6-dichlorobenzyl)—L-tyrosine;N-{2-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-methyl-propanoyl}-O-(2,6-di-chlorobenzyl)-L-tyrosine;N-{2-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-ethyl-butanoyl}-0-(2,6-dichlorobenzyl)-L-tyrosine;andN-{1-[4-(4-hydroxyphenyl)piperazine-1-ylcarbonyl]-2-ethyl-butanoyl}-O-(2,6-dichlorobenzyl)-L-tyrosine.21. A pharmaceutical composition containing a phenylalanine derivativeor a pharmaceutically acceptable salt thereof according to claim 1 as anactive ingredient.
 22. A pharmaceutical composition containing aphenylalanine derivative or a pharmaceutically acceptable salt thereofaccording to claim 17 as an active ingredient.
 23. An α 4 integrinantagonist containing a phenylalanine derivative or a pharmaceuticallyacceptable salt thereof according to claim 1 as an active ingredient.24. An α 4 integrin antagonist containing a phenylalanine derivative ora pharmaceutically acceptable salt thereof according to claim 17 as anactive ingredient.
 25. A therapeutic agent or preventive agent forinflammatory diseases in which α 4 integrin-depending adhesion processparticipates in the pathology, which contains a phenylalanine derivativeor a pharmaceutically acceptable salt thereof according to claim 1 as anactive ingredient.
 26. A therapeutic agent or preventive agent forinflammatory diseases in which α 4 integrin-depending adhesion processparticipates in the pathology, which contains a phenylalanine derivativeor a pharmaceutically acceptable salt thereof according to claim 17 asan active ingredient.
 27. A therapeutic agent or preventive agent forrheumatoid arthritis, inflammatory bowel diseases, systemicerythematodes, multiple sclerosis, Sjogren's syndrome, asthma,psoriasis, allergy, diabetes, cardiovascular diseases, arterialsclerosis, restenosis, tumor proliferation, tumor metastasis andtransplantation rejection, which contains a phenylalanine derivative ora pharmaceutically acceptable salt thereof according to claim 1 as anactive ingredient.
 28. A therapeutic agent or preventive agent forrheumatoid arthritis, inflammatory bowel diseases, systemicerythematodes, multiple sclerosis, Sjogren's syndrome, asthma,psoriasis, allergy, diabetes, cardiovascular diseases, arterialsclerosis, restenosis, tumor proliferation, tumor metastasis andtransplantation rejection, which contains a phenylalanine derivative ora pharmaceutically acceptable salt thereof according to claim 17 as anactive ingredient.